U.S. patent number 7,807,677 [Application Number 11/884,224] was granted by the patent office on 2010-10-05 for hiv protease inhibitors.
This patent grant is currently assigned to Medivir AB. Invention is credited to Jenny Ekegren, Anders Hallberg, Mahalingam Kannan, Bertil Samuelsson, Hans Wallberg.
United States Patent |
7,807,677 |
Ekegren , et al. |
October 5, 2010 |
HIV protease inhibitors
Abstract
Compounds of the formula I: ##STR00001## wherein R.sup.1,
R.sup.2, X and N are as defined in the specification; E is N, CH;
A' and A'' are terminal groups as defined in the specification. The
compounds have utility as HIV-1 protease inhibitors.
Inventors: |
Ekegren; Jenny (Huddinge,
SE), Hallberg; Anders (Huddinge, SE),
Wallberg; Hans (Huddinge, SE), Samuelsson; Bertil
(Huddinge, SE), Kannan; Mahalingam (Huddinge,
SE) |
Assignee: |
Medivir AB (Huddinge,
SE)
|
Family
ID: |
36128513 |
Appl.
No.: |
11/884,224 |
Filed: |
February 9, 2006 |
PCT
Filed: |
February 09, 2006 |
PCT No.: |
PCT/EP2006/001135 |
371(c)(1),(2),(4) Date: |
March 27, 2008 |
PCT
Pub. No.: |
WO2006/084688 |
PCT
Pub. Date: |
August 17, 2006 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080249102 A1 |
Oct 9, 2008 |
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Foreign Application Priority Data
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Feb 10, 2005 [SE] |
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0500307 |
Oct 25, 2005 [SE] |
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0502352 |
Nov 8, 2005 [SE] |
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0502468 |
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Current U.S.
Class: |
514/252.1;
514/476; 514/357; 546/332; 544/336; 560/27; 560/24; 549/441;
549/32; 514/464; 514/443 |
Current CPC
Class: |
C07C
275/24 (20130101); C07D 263/52 (20130101); C07C
271/22 (20130101); C07D 261/08 (20130101); A61P
43/00 (20180101); C07D 241/12 (20130101); C07C
311/06 (20130101); C07D 317/58 (20130101); C07D
333/58 (20130101); C07D 307/33 (20130101); A61P
31/18 (20180101); C07D 213/42 (20130101); C07D
303/48 (20130101); A61P 37/04 (20180101); C07C
2602/08 (20170501) |
Current International
Class: |
C07C
271/22 (20060101); C07D 241/12 (20060101); C07C
311/06 (20060101); A61K 31/38 (20060101); A61K
31/325 (20060101); A61K 31/17 (20060101); A61K
31/18 (20060101); C07D 213/42 (20060101); C07C
275/24 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
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6291687 |
September 2001 |
Classon et al. |
6489364 |
December 2002 |
Classon et al. |
|
Foreign Patent Documents
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|
0480 714 |
|
Apr 1992 |
|
EP |
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WO 92/15319 |
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Sep 1992 |
|
WO |
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WO 97/40029 |
|
Oct 1997 |
|
WO |
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WO98/45330 |
|
Oct 1998 |
|
WO |
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WO 2006/084688 |
|
Aug 2006 |
|
WO |
|
Other References
Jenny K. Ekegren et al., "A New Class of HIV-1 Protease Inhibitors
Containing a Tertiary Alcohol in the Transition-State Mimicking
Scaffold", J. Med. Chem.: 48, 8098-8102 (2005). cited by other
.
Johanna Wachtmeister et al., , Tetrahedron 56: 3219-3225 (2000).
cited by other .
Guido Bold et al. "New Aza-Dipeptide Analogues as Potent and Orally
Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical
Development," J.Med. Chem: 41, 3387-3401 (1998). cited by
other.
|
Primary Examiner: Powers; Fiona T
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch, LLP
Claims
The invention claimed is:
1. A compound of the formula I: ##STR00135## wherein R.sup.1 is
--R.sup.1', +OR.sup.1', --SR.sup.1', R.sup.1' is
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3 alkanediylcarbocyclyl or
C.sub.0-C.sub.3 alkanediylheterocyclyl, any of which is optionally
substituted with up to 3 substituents independently selected from
R.sup.10; R.sup.2 is C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3
alkanediylcarbocyclyl, C.sub.0-C.sub.3 alkanediylheterocyclyl, any
of which is optionally substituted with up to 3 substituents
independently selected from R.sup.10; X is H, F, OH,
C.sub.1-C.sub.3Alk or C.sub.0-C.sub.3 alkanediyl-O--C.sub.1-C.sub.3
alkyl; L is OH, F, NH.sub.2, --NHC.sub.1-C.sub.3Alk;
--N(C.sub.1-C.sub.3Alk).sub.2; n is 0, 1 or 2; E is N, CH; A' is a
bicyclic ring system comprising a first 5 or 6 membered saturated
ring optionally containing an oxygen hetero atom and optionally
substituted with hydroxy and/or methyl, having fused thereto a
second 5 or 6 membered unsaturated ring optionally containing one
or two hetero atoms selected from S, O and N, and optionally
substituted with mono- or di-fluoro; or A' is a group of formula
(II), (II'), (III) or (IV): ##STR00136## wherein; R.sup.3 is H; or
R.sup.3 is C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3
alkanediylcarbocyclyl, C.sub.0-C.sub.3 alkanediylheterocyclyl, any
of which is optionally substituted with up to three substituents
independently selected from R.sup.11; R.sup.4 is
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3 alkanediylcarbocyclyl,
C.sub.0-C.sub.3 alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10; R.sup.5 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10; Z is bond, --NH--, --O--; Rx is H,
C.sub.1-C.sub.3alkyloxy, C.sub.1-C.sub.3 straight or branched alkyl
optionally substituted with halo, hydroxy, C.sub.1-C.sub.3alkyloxy;
or Rx, together with the adjacent carbon atom, defines a fused
furanyl or pyranyl ring which is optionally substituted with halo
or C.sub.1-C.sub.3Alk; t is 0 or 1; A'' is a group of formula (V),
(VI) (VII) or (VIII); ##STR00137## wherein; R.sup.8 is H; or
R.sup.8 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any which is optionally
substituted with up to three substituents independently selected
from R.sup.11; R.sup.9 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10; W is a bond, --NR.sup.13-- or --O--; R.sup.13 is H
or C.sub.1-C.sub.6Alk, or R.sup.13 and R.sup.9 together with the N
atom to which they are attached define a saturated, partially
saturated or aromatic N-containing ring containing 5 or 6 ring
atoms, which is optionally substituted with up to three
substituents selected from R.sup.10; D is O or NH; Ry is H or Ry,
together with the adjacent C atom defines a fused furan or pyran
ring; Q is O, CHR.sup.8 or a bond; R.sup.15 is carbocyclyl or
heterocyclyl, any of which is optionally substituted with up to
three substituents independently selected from C.sub.1-C.sub.3Alk,
hydroxy, oxo, halo; q and r are independently 0 or 1; R.sup.10 is
halo, oxo, cyano, azido, nitro, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, Y--O--Rb,
Y--C.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb,
Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb,
Y--C(.dbd.O)ORb or Y--NRaC(.dbd.O)ORb; wherein; Y is a bond or
C.sub.1-C.sub.3alkanediyl; Ra is H or C.sub.1-C.sub.3Alk; Rb is H
or C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl; p is 1 or 2; R.sup.11 is
halo, oxo, cyano, azido, nitro, C.sub.1-C.sub.3Alk, Y--NRaRa',
Y--O--Ra; wherein; Ra' is H or C.sub.1-C.sub.3Alk; or Ra and Ra'
and the nitrogen atom to which they are attached define
pyrrolidine, morpholine, piperidine or piperazine which is
optionally 4-substituted with methyl or acetyl; C.sub.1-C.sub.6Alk
is a straight or branched aliphatic carbon chain containing from 1
to 6 carbon atoms, optionally having at least one unsaturated bond;
C.sub.1-C.sub.5Alk is a straight or branched aliphatic carbon chain
containing from 1 to 5 carbon atoms, optionally having at least one
unsaturated bond; C.sub.1-C.sub.4Alk is a straight or branched
aliphatic carbon chain containing from 1 to 4 carbon atoms,
optionally having at least one unsaturated bond; C.sub.1-C.sub.3Alk
is a straight or branched aliphatic carbon chain containing from 1
to 3 carbon atoms, optionally having at least one unsaturated bond;
or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein R.sup.1 is optionally
substituted C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl.
3. A compound according to claim 2, wherein R.sup.1' is optionally
substituted carbocyclyl or heterocyclyl.
4. A compound according to claim 3, wherein the R.sup.1'
carbocyclyl moiety is optionally substituted phenyl or the R.sup.1'
heterocyclyl moiety is optionally substituted pyridyl, pyrazinyl,
pyrimidinyl or pyridazinyl.
5. A compound according to claim 1, wherein at least one optional
substituent to R.sup.1' is selected from halo, oxo, cyano,
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, and Y--O--Rb;
where Y is a bond or C.sub.1-C.sub.3Alk, Ra is H or
C.sub.1-C.sub.3Alk and Rb is H or C.sub.1-C.sub.3Alk.
6. A compound according to claim 5, wherein the optional
substituent to R.sup.1' is selected from fluoro,
C.sub.1-C.sub.3Alk, C.sub.0-C.sub.1 alkanediylcarbocyclyl, or
C.sub.0-C.sub.1alkanediylheterocyclyl.
7. A compound according to claim 4, wherein R.sup.1' is mono- or
di-halo substituted phenyl.
8. A compound according to claim 7 wherein R.sup.1' is mono- or
di-fluoro substituted phenyl.
9. A compound according to claim 4 wherein R.sup.1' is phenyl.
10. A compound according to claim 1, with the stereochemistry shown
in the partial structure. ##STR00138##
11. A compound according to claim 1 wherein R.sup.2 is optionally
substituted C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.1-C.sub.3alkanediylheterocyclyl.
12. A compound according to claim 11, wherein R.sup.2 is optionally
substituted carbocyclyl or heterocyclyl.
13. A compound according to claim 12, wherein the R.sup.2
carbocyclyl moiety is optionally substituted phenyl or the R.sup.2
heterocyclyl moiety is optionally substituted pyridyl, pyrazinyl,
pyrimidinyl or pyridazinyl.
14. A compound according to claim 1, wherein at least one optional
substituent to R.sup.2 is selected from halo, oxo, cyano,
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, and Y--O--Rb;
where Y is a bond or C.sub.1-C.sub.3Alk, Ra is H or
C.sub.1-C.sub.3Alk and Rb is H or C.sub.1-C.sub.3Alk.
15. A compound according to claim 14, wherein the optional
substituent to R.sup.2 is selected from fluoro, C.sub.1-C.sub.3Alk,
C.sub.0-C.sub.1 alkanediylcarbocyclyl, or
C.sub.0-C.sub.1alkanediylheterocyclyl.
16. A compound according to claim 13, wherein R.sup.2 is
carbocyclyl or heterocyclyl substituted phenyl.
17. A compound according to claim 16, wherein R.sup.2 is aryl or
heteroaryl substituted phenyl.
18. A compound according to claim 17 wherein R.sup.2 is pyridyl
substituted phenyl.
19. A compound according to claim 1, wherein X is H or OH.
20. A compound according to claim 1, wherein n is 1.
21. A compound according to claim 1, wherein E is N.
22. A compound according to claim 1, wherein A' is a group of
formula (II) or (IV).
23. A compound according to claim 22, wherein R.sup.3 is H,
optionally substituted C.sub.1-C.sub.6Alk or optionally substituted
C.sub.0-C.sub.3alkanediyiheterocyciyl.
24. A compound according to claim 23, wherein R.sup.3 is H or
optionally substituted C.sub.1-C.sub.6Alk.
25. A compound according to claim 23, wherein R.sup.3 is
C.sub.1-C.sub.6Alk optionally substituted with halo.
26. A compound according to claim 23, wherein the optional
substituent to R.sup.3 is oxo, cyano or halo or Y--O--Ra, where Y
is a bond or C.sub.1-C.sub.3Alk and Ra is H or
C.sub.1-C.sub.3Alk.
27. A compound according to claim 1, wherein R.sup.4 is optionally
substituted C.sub.1-C.sub.6Alk.
28. A compound according to claim 1, wherein the optional
substituent to R.sup.4 is halo, oxo, cyano, azido, nitro,
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb or Y--O--Rb
wherein; Y is a bond or C.sub.1-C.sub.3Alk; Ra is H or
C.sub.1-C.sub.3Alk; Rb is H or C.sub.1-C.sub.6Alk,
0.sub.1-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl.
29. A compound according to claim 28 wherein the optional
substituent is halo, oxo, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.10-C.sub.3alkanediylheterocyclyl or Y--O--Rb.
30. A compound according to claim 29, wherein the optional
substituent is halo or Y--O--Rb.
31. A compound according to claim 30, wherein R.sup.4 is
methyl.
32. A compound according to claim 22, with the stereochemistry
shown in the partial structure ##STR00139##
33. A compound according to claim 22, wherein Rx is hydroxymethyl,
1-hydroxyethyl, 1-hydroxypropyl, fluoromethyl, 1-fluoroethyl or
1-fluoropropyl.
34. A compound according to claim 22, wherein Rx is methoxymethyl,
ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methoxypropyl or
1-ethoxypropyl.
35. A compound according to claim 22, wherein A' is
##STR00140##
36. A compound according to claim 1, wherein A' is a bicyclic ring
system comprising a first 5 or 6 membered saturated ring optionally
containing an oxygen hetero atom, and optionally substituted with
hydroxy or methyl, having fused thereto a second 5 or 6 membered
unsaturated ring optionally containing one or two hetero atoms
selected from S, O and N, and optionally mono- or di-fluoro
substituted.
37. A compound according to claim 36, wherein the bond to the rest
of the molecule extends from carbon 1 of said saturated ring.
38. A compound according to claim 37, wherein the optional hydroxy
substituent is at carbon 2 of said saturated ring.
39. A compound according to claim 37, wherein the oxygen hetero
atom is position 3 of a 5 membered saturated ring or position 4 of
a 6 membered saturated ring.
40. A compound according to claim 36, wherein said second ring is
5-membered and comprises a sulphur hetero atom or an oxygen hetero
atom.
41. A compound according to claim 36, wherein said second ring is
optionally substituted phenyl.
42. A compound according to claim 41, wherein the substituent is
mono- or di-fluoro.
43. A compound according to claim 36, wherein A' is:
##STR00141##
44. A compound according to claim 36, wherein A' is
##STR00142##
45. A compound according to claim 1, wherein A'' is of the formula
(V).
46. A compound according to claim 45, wherein R.sup.8 is H,
optionally substituted C.sub.1-C.sub.6Alk or optionally substituted
C.sub.0-C.sub.3alkanediylcarbocyclyl.
47. A compound according to claim 46, wherein R.sup.8 is H or
optionally substituted C.sub.1-C.sub.6Alk.
48. A compound according to claim 45, wherein the optional
substituent to R.sup.8 is oxo, cyano, C.sub.1-C.sub.3Alk or halo or
Y--O--Ra; where Y is a bond or C.sub.1-C.sub.3Alk; Ra is H or
C.sub.1-C.sub.3Alk.
49. A compound according to claim 45, wherein R.sup.9 is optionally
substituted C.sub.1-C.sub.6Alk or
C.sub.0-C.sub.3alkanediylcarbocyclyl.
50. A compound according to claim 49, wherein R.sup.9 is optionally
substituted methyl.
51. A compound according to claim 45, wherein the optional
substituent to R.sup.9 is halo, oxo, cyano, azido, nitro,
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb or Y--O--Rb
wherein; Y is a bond or C.sub.1-C.sub.3Alk; Ra is H or
C.sub.1-C.sub.3Alk; Rb is H or C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl.
52. A compound according to claim 51, wherein the optional
substituent is halo, oxo, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl or Y--O--Rb.
53. A compound according to claim 52, wherein R.sup.9 is
methyl.
54. A compound according to claim 45 wherein W is --O--.
55. A compound according to claim 45 with the stereochemistry shown
in the partial structure: ##STR00143##
56. A pharmaceutical composition comprising a compound as defined
in claim 1 and a pharmaceutically acceptable carrier or diluent
therefore.
57. A pharmaceutical composition according to claim 56, further
comprising 1 to 3 additional HIV antivirals.
58. A method of treatment for HIV infection comprising
administering an effective amount of a compound as defined in claim
1 to an individual infected or threatened with HIV infection.
59. The compound according to claim 25 wherein R.sup.3 is isopropyl
or t-butyl.
60. The compound according to claim 26 wherein R.sup.3 is
Y--O--Ra.
61. The compound according to claim 27 wherein R.sup.4 is methyl or
optionally substituted methyl.
62. The compound according to claim 47 wherein R.sup.8 is isopropyl
or t-butyl.
63. The compound according to claim 48 wherein R.sup.8 is Y--O--Ra
or halo.
Description
This application is the National Phase Under 35 U.S.C. .sctn.371 of
PCT International Application No. PCT/EP06/01135 which has an
International filing date of Feb. 9, 2006, which designates the
United States of America, and claims priority to Swedish Patent
Application No. 0500307-4, which has a filing date of Feb. 10,
2005, Swedish Patent Application No. 0502352-8, which has a filing
date of Oct. 25, 2005 and Swedish Patent Application No. 0502468-2,
which has a filing date of Oct. 9, 2005, the entire contents of all
applications listed above are hereby incorporated by reference.
BACKGROUND TO THE INVENTION
Two distinct retroviruses, human immunodeficiency virus (HIV)
type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to
the immunosuppressive disease, acquired immunodeficiency syndrome
(AIDS). HIV seropositive individuals are initially asymptomatic but
typically develop AIDS related complex (ARC) followed by AIDS.
Affected individuals exhibit severe immunosuppression, which
predisposes them to debilitating and ultimately fatal opportunistic
infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus
following its own complex life cycle. The virion life cycle begins
with the virion attaching itself to the host human T-4 lymphocyte
immune cell through the bonding of a glycoprotein on the surface of
the virion's protective coat with the CD4 glycoprotein on the
lymphocyte cell. Once attached, the virion sheds its glycoprotein
coat, penetrates into the membrane of the host cell, and uncoats
its RNA. The virion enzyme, reverse transcriptase, directs the
process of transcribing the RNA into single-stranded DNA. The viral
RNA is degraded and a second DNA strand is created. The now
double-stranded DNA is integrated into the human cell's genes and
those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into
viral RNA. The viral RNA is translated into the precursor gag-pol
fusion polyprotein, the polyprotein is then cleaved by the HIV
protease enzyme to yield the mature viral proteins. Thus, HIV
protease is responsible for regulating a cascade of cleavage events
that lead to the virus particle's maturing into a virus that is
capable of full infectivity.
The typical human immune system response, killing the invading
virion, is taxed because the virus infects and kills the immune
system's T cells. In addition, viral reverse transcriptase, the
enzyme used in making a new virion particle, is not very specific,
and causes transcription mistakes that result in continually
changed glycoproteins on the surface of the viral protective coat.
This lack of specificity decreases the immune system's
effectiveness because antibodies specifically produced against one
glycoprotein may be useless against another, hence reducing the
number of antibodies available to fight the virus. The virus
continues to reproduce while the immune response system continues
to weaken. Eventually, the HIV largely holds free reign over the
body's immune system, allowing opportunistic infections to set in
and without the administration of antiviral agents,
immunomodulators, or both, death may result.
There are at least three critical points in the virus's life cycle
which have been identified as possible targets for antiviral drugs:
(1) the initial attachment of the virion to the T-4 lymphocyte or
macrophage site, (2) the transcription of viral RNA to viral DNA
(reverse transcriptase, RT), and (3) the processing of gag-pol
protein by HIV protease.
The genomes of retroviruses encode a protease that is responsible
for the proteolytic processing of one or more polyprotein
precursors such as the pol and gag gene products. Retroviral
proteases most commonly process the gag precursor into the core
proteins, and also process the pol precursor into reverse
transcriptase and retroviral protease. The correct processing of
the precursor polyproteins by the retroviral protease is necessary
for the assembly of the infectious virions. It has been shown that
in vitro mutagenesis that produces protease-defective virus leads
to the production of immature core forms which lack infectivity.
Therefore, retroviral protease inhibition provides an attractive
target for antiviral therapy.
As evidenced by the protease inhibitors presently marketed and in
clinical trials, a wide variety of compounds have been studied as
potential HIV protease inhibitors. The first inhibitor of so-called
retroviral aspartate protease to be approved for combating the
infection was saquinavir. Since then others have followed including
indinavir (Merck), ritonavir (Abbott), amprenavir and its prodrug
amprenavir phosphate (Vertex/GSK), lopinavir (Abbott), nelfinavir
(Aguoron/Pfizer), tipranavir (Pharmacia/Boehringer) and atazanavir
(Novartis/BMS).
Each of these prior art compounds has liabilities in the
therapeutic context resulting in sub-optimal treatment regimes,
side effects such as lipodystrophy and poor patient compliance. In
conjunction with the replicative infidelity of the HIV genetic
machinery and the very high viral turnover in vivo, the sub-optimal
performance and pharmacokinetics of prior art HIV protease
inhibitors enable the rapid generation of drug escape mutants. This
in turn dramatically limits the effective treatment length of
current HIV drugs as HIV quickly becomes resistant and/or patients
develop physical or psychological aversions to the drugs themselves
or their side effects.
The aim of the present invention is to provide a novel type of
compound that is equipped, especially, with a high degree of
inhibitory activity against virus replication in cells, high
antiviral activity against numerous virus strains, including those
which are resistant to known compounds, such as saquinavir,
ritonavir and indinavir, and especially advantageous
pharmacological properties, for example good pharmacokinetics, such
as high bioavailability and high blood levels, and/or high
selectivity.
In accordance with the invention, there is provided a compound of
the formula I:
##STR00002## wherein
R.sup.1 is --R.sup.1', --OR.sup.1', --SR.sup.1',
R.sup.1' is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-3alkanediylheterocyclyl, any of which is optionally
substituted with up to 3 substituents independently selected from
R.sup.10;
R.sup.2 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to 3 substituents independently selected from
R.sup.10;
X is H, F, OH, C.sub.1-C.sub.3Alk or
C.sub.0-C.sub.3alkanediyl-O--C.sub.1-C.sub.3alkyl;
L is OH, F, NH.sub.2, --NHC.sub.1-C.sub.3Alk;
--N(C.sub.1-C.sub.3Alk).sub.2;
n is 0, 1 or 2;
E is N or CH;
A' is a bicyclic ring system comprising a first 5 or 6 membered
saturated ring optionally containing an oxygen hetero atom and
optionally substituted with hydroxy and/or methyl, having fused
thereto a second 5 or 6 membered unsaturated ring optionally
containing one or two hetero atoms selected from S, O and N, and
optionally substituted with mono- or di-fluoro; or
A' is a group of formula (II), (II'), (III) or (IV):
##STR00003## wherein,
R.sup.3 is H; or R.sup.3 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.11;
R.sup.4 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10;
R.sup.5 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10;
Z is a bond, --NH-- or --O--;
Rx is H, C.sub.1-C.sub.3alkyloxy, C.sub.1-C.sub.3 straight or
branched alkyl optionally substituted with halo, hydroxy,
C.sub.1-C.sub.3alkyloxy; or Rx, together with the adjacent carbon
atom, defines a fused furanyl or pyranyl ring which is optionally
substituted with halo or C.sub.1-C.sub.3Alk;
t is 0 or 1;
A'' is a group of formula (V), (VI) (VII) or (VIII);
##STR00004## wherein;
R.sup.8 is H; or R.sup.8 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-.sub.3alkanediylheterocyclyl, any which is optionally
substituted with up to three substituents independently selected
from R.sup.11
R.sup.9 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10;
W is a bond, --NR.sup.13-- or --O--;
R.sup.13 is H, C.sub.1-C.sub.6Alk or R.sup.13 and R.sup.9 together
with the N atom to which they are attached define a saturated,
partially saturated or aromatic N-containing ring containing 5 or 6
ring atoms, which is optionally substituted with up to three
substituents selected from R.sup.10;
D is O or NH;
Ry is H or Ry, together with the adjacent C atom defines a fused
furan or pyran ring;
Q is O, CHR.sup.8 or a bond;
R.sup.15 is carbocyclyl or heterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from C.sub.1-C.sub.3Alk, hydroxy, oxo, halo;
r and q are independently 0 or 1;
R.sup.10 is halo, oxo, cyano, azido, nitro, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, Y--O--Rb,
Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb,
Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb,
Y--C(.dbd.O)ORb or Y--NRaC(.dbd.O)ORb; wherein;
Y is a bond or C.sub.1-C.sub.3alkanediyl;
Ra is H or C.sub.1-C.sub.3Alk;
Rb is H or C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl
or C.sub.0-C.sub.3alkanediylheterocyclyl;
p is 1 or 2;
R.sup.11 is halo, oxo, cyano, azido, nitro, C.sub.1-C.sub.3Alk,
Y--NRaRa', Y--O--Ra; wherein;
Ra' is H or C.sub.1-C.sub.3Alk; or Ra and Ra' and the nitrogen atom
to which they are attached define pyrrolidine, morpholine,
piperidine or piperazine which is optionally 4-substituted with
methyl or acetyl;
and pharmaceutically acceptable salts thereof.
A further aspect of the invention embraces a pharmaceutical
composition comprising a compound as defined above and a
pharmaceutically acceptable carrier or diluent therefore. A still
further aspect of the invention envisages the use of a compound as
defined above in the manufacture of a medicament for the
prophylaxis or treatment of HIV infection. An additional aspect of
the invention provides a method of medical treatment or prophylaxis
for HIV infection comprising the administration of an effective
amount of a compound as defined in above to an individual infected
or threatened with HIV infection.
Without in any way wishing to be bound by theory, or the ascription
of tentative binding modes for specific variables, the notional
concepts P1, P1', P2 and P2' as used herein are provided for
convenience only and have substantially their conventional
meanings, as illustrated by Schechter & Berger, (1976) Biochem
Biophys Res Comm 27 157-162, and denote those portions of the
inhibitor believed to fill the S1, S1', S2 and S2' subsites
respectively of the enzyme, where S1 is adjacent and S2 remote from
the cleavage site on one side and S1' is adjacent and S2' remote
from the cleavage site on the other side. Regardless of binding
mode, the compounds defined by Formula I are intended to be within
the scope of the invention. It is conceivable that R.sup.1 and
R.sup.2 respectively fill the S1 and S1' subsites, whereas A' and
A'' interact with the S2 and S2', but also conceivable with the
inverse arrangement.
Conveniently, the compounds of the invention display at least 75%,
preferably at least 90%, such as in excess of 95%, enantiomeric
purity around the carbon shared by the hydroxyl group and the
R.sup.1 methylene function depicted in formula I. It is currently
preferred that the compounds exhibit a high degree of enantiomeric
purity of the steroisomeres as shown in the partial structure:
##STR00005##
Group X can be either R or S stereochemistry.
As defined above X is H, OH, C.sub.1-C.sub.3Alk or
C.sub.0-C.sub.3alkanediyl-O--C.sub.1-C.sub.3alkyl. Convenient
values for X include OH and
C.sub.0-C.sub.3alkanediyl-O--C.sub.1-C.sub.3alkyl especially
methoxy (i.e. C.sub.0) and hydroxymethyl. A currently favoured
value for X is H or OH.
As recited above, L is OH, F, NH.sub.2, NHC.sub.1-C.sub.3Alk,
N(C.sub.1-C.sub.3Alk).sub.2, wherein the NHC.sub.1-C.sub.3Alk and
N(C.sub.1-C.sub.3Alk).sub.2 preferably are NHMe and NHMe.sub.2
respectively. A currently preferred value for L is fluoro and a
more preferred value is OH.
The compounds of the invention can have 2 chain atoms between the
carbonyl depicted in formula I and function E (i.e. n is 0). Other
embodiments of the invention comprise 3 or 4 chain atoms between
the carbonyl and function E, i.e. n is 1 or 2 respectively. In
favoured embodiments of the invention the compounds have 3 chain
atoms between the carbonyl and function E, i.e. n is 1.
Conveniently, the compounds of the invention comprise a hydrazide
function, that is E is N, as it is believed that this configuration
pitches the R.sup.2-methylene side chain at an advantageous angle
relative to the S1' (or S1) pocket of HIV protease, for example
when A'' is according to formula V. However the optimal angle will,
of course depend on other interactions along the backbone, side
chains and termini of the compounds and thus additional embodiments
of the invention comprise CH at function E.
As defined above, R.sup.1 is R.sup.1', OR.sup.1' or SR.sup.1'
wherein R.sup.1' is C.sub.1-C.sub.6allyl, but is especially
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-.sub.3alkanediylheterocyclyl. Typical examples of such
species are recited below. Any of these species is optionally
substituted with up to 3 substituents independently selected from
R.sup.10 as defined above. Convenient optional substituents to
R.sup.1' include one or two substituents selected from halo, oxo,
cyano, C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, Y--O--Rb; where Y
is a bond or C.sub.1-C.sub.3Alk, Ra is H or C.sub.1-C.sub.3Alk and
Rb is H or C.sub.1-C.sub.3Alk. Particularly preferred substituents
include fluoro, C.sub.1-C.sub.3Alk,
C.sub.0-C.sub.1alkanediylcarbocyclyl,
C.sub.0-C.sub.1alkanediylheterocyclyl.
Conveniently, the C.sub.0-C.sub.3alkanediyl linker moiety of such
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-3alkanediylheterocyclyl species as R.sup.1 or the optional
substituent thereto defines methylene or even more preferably a
bond, i.e. R.sup.1' or the substituent is simply an optionally
substituted carbocyclyl or heterocyclyl, such as optionally
substituted phenyl or optionally substituted pyridyl, pyrazinyl,
pyrimidinyl or pyridazinyl.
Preferably R.sup.1 is R.sup.1' or OR.sup.1'.
In one embodiment of the present invention the R.sup.10 substituent
of R.sup.1 is Y--O--Rb where Y is a bond and Rb is an optionally
substituted C.sub.0-C.sub.3alkanediylaryl or
C.sub.0-C.sub.3alkanediylheteroaryl. The optional substituent is
preferably C.sub.1-C.sub.3Alk, such as methyl
Preferred structures for R.sup.1 according to this embodiment
include:
##STR00006##
According, other suitable values for R.sup.1 include phenyl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl, pyrimidinyl-4-,
pyrazin-2-yl, pyrazin-3-ylyl or pyridazin-3-yl, pyridazin-4-yl or
triazinyl; or mono- or di-halo substituted phenyl, such mono- or
di-fluoro substituted phenyl.
As defined above, R.sup.2 is C.sub.1-C.sub.6Alk, but especially
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-3alkanediylheterocyclyl, any of which species can be
substituted with up to 3 substituents independently selected from
R.sup.10. The optional substituent is preferably one or two members
chosen from halo, oxo, cyano, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb, Y--O--Rb; where Y
is a bond or C.sub.1-C.sub.3Alk, Ra is H or C.sub.1-C.sub.3Alk and
Rb is H or C.sub.1-C.sub.3Alk. Currently favoured substituents
include fluoro, C.sub.1-C.sub.3Alk, methylenecarbocyclyl or
methyleneheterocyclyl, but especially a substituent such as
optionally substituted carbocyclyl or heterocyclyl, for example in
the para position of the R cyclic group.
Conveniently, the C.sub.0-C.sub.3alkanediyl linker moiety of such
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl species as R.sup.2 or the
optional substituent thereto defines methylene or even more
preferably a bond, i.e. R.sup.2 or the substituent is simply an
optionally substituted carbocyclyl or heterocyclyl, such as
optionally substituted phenyl or optionally substituted pyridyl,
pyrazinyl, pyrimidinyl or pyridazinyl
Accordingly suitable values for R.sup.2 include phenyl, pyrid-2-yl,
pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl, pyrimidiny-4-yl,
pyrazin-2-yl, pyrazin-3-ylyl or pyridazin-3-yl, pyridazin-4-yl or
triazinyl; or phenyl substituted, especially in the para position
with an aryl carbocyclic ring such as phenyl or heterocyclic ring,
such as heteroarylic group as defined below, for example
pyrid-2-yl, pyrid-3-yl or pyrid-4-yl.
Turning now to the terminal amide A', one convenient embodiment
comprises a bicyclic ring system comprising a first 5 or 6 membered
saturated ring optionally containing an oxygen hetero atom, and
optionally substituted with hydroxy or methyl, having fused thereto
a second 5 or 6 membered unsaturated ring optionally containing one
or two hetero atoms selected from S, O and N, and optionally mono-
or di-fluoro substituted.
Conveniently in this embodiment the bond to the amide and rest of
the molecule extends from carbon 1 of said saturated ring. Suitably
the optional hydroxy substitutent in this embodiment is at carbon 2
of said saturated ring. Alternatively an oxygen hetero atom is
provided, typically at position 3 of a 5 membered saturated ring or
position 4 of a 6 membered saturated ring.
The second ring in this embodiment of A' is conveniently 5-membered
and comprises a sulphur hetero atom or an oxygen hetero atom.
Alternatively, the said second ring is typically a fused pyridyl as
described in WO9845330 or an optionally substituted phenyl, for
example a fused phenyl wherein the substituent is mono- or
di-fluoro.
Representative A' groups in this embodiment of the invention
include:
##STR00007##
An alternative embodiment of the compounds of the invention
includes those wherein A' is a group of formula (II), thereby
defining a compound of the formula:
##STR00008##
A further alternative embodiment of the compounds of the invention
includes those wherein A' is a group of formula (II'), thereby
defining a compound of the formula:
##STR00009##
As recited above R.sup.3 is H; or R.sup.3 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.11. Convenient values for R.sup.3 include optionally
substituted C.sub.0-C.sub.3alkylheterocycylyl and especially H or
optionally substituted C.sub.1-C.sub.6Alk. Favoured R.sup.3 values
include C.sub.1-C.sub.6Alk such as isopropyl or t-butyl optionally
substituted with hydroxy or methoxy or halo, such as fluoro.
Preferred values for R.sup.3 are isopropyl, t-butyl,
2-fluoro-1-methylethyl, 2-hydroxy-1-methylethyl,
2-methoxy-1-methylethyl, 2-fluoro-1,1-dimethylethyl,
2-hydroxy-1,1-dimethylethyl and 2-methoxy-1,1-dimethylethyl.
The optional substituent to R.sup.3 is as defined above.
Representative values include oxo, cyano or especially halo or
Y--O--Ra, where Y is a bond or C.sub.1-C.sub.3Alk and Ra is H or
C.sub.1-C.sub.3Alk.
As recited above R.sup.4 in Formulae I, IIa and II'a is
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10. Favoured values of R.sup.4 include optionally
substituted C.sub.1-C.sub.6Alk, especially methyl or ethyl or
optionally substituted methyl or ethyl.
Convenient optional substituents to R.sup.4 include halo, oxo,
cyano, azido, nitro, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb or Y--O--Rb
wherein;
Y is a bond or C.sub.1-C.sub.3Alk;
Ra is H or C.sub.1-C.sub.3Alk;
Rb is H or C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl
or C.sub.0-C.sub.3alkanediylheterocyclyl.
Preferred values for R.sup.4 are fluoroethyl, difluoroethyl,
trifluoroethyl and methoxyethyl.
Preferred optional substituents to R.sup.4 include halo, oxo,
C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl or Y--O--Rb, especially halo
or Y--O--Rb.
Formula II may comprise the S or R stereochemistry at the chiral
centre to which R.sup.3 is attached, or a racemate thereof, but it
is currently preferred that it has the stereochemistry shown in the
partial structure:
##STR00010##
Alternatively A' may comprise the substructure:
##STR00011## where R.sup.3 is H; or R.sup.3 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.11; R.sup.5 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10; and Z is bond, --NH--, --O--; Preferred values for
R.sup.3 are as defined above in respect of formula II.
Formula III may comprise the S or R stereochemistry at the chiral
centre to which R.sup.3 is attached, or a racemate thereof, but it
is currently preferred that it has the stereochemistry shown in the
partial structure:
##STR00012##
Currently preferred values for Z is O. Favoured values of R.sup.5
include optionally substituted C.sub.1-C.sub.6Alk, especially
methyl or optionally substituted methyl.
A favoured value for A' is formula IV, thus defining a compound of
the formula
##STR00013##
Representative values for formula IV include monocyclic furans
where Rx is H, C.sub.1-C.sub.3alkyloxy, C.sub.1-C.sub.3 straight or
branched alkyl optionally substituted with halo, hydroxy,
C.sub.1-C.sub.3alkyloxy. Representative values within this series
include those wherein Rx is H, or wherein Rx is C.sub.1-C.sub.3Alk
substituted at chain carbon 1 with halo, hydroxy or
C.sub.1-C.sub.2Alk. Favoured values include those wherein Rx is
hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, fluoromethyl,
1-fluoroethyl or 1-fluoropropyl and those wherein Rx is
methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl,
1-methoxypropyl or 1-ethoxypropyl. Specially preferred compounds
according to formula IVa are those wherein n is 1 and/or L is
OH.
Alternatively Rx defines a further furanyl or pyranyl ring fused to
the depicted furan and optionally substituted with halo or
C.sub.1-C.sub.3Alk. Representative examples include those wherein
the heterocyclic oxygen is located as follows:
##STR00014##
Turning now to the order other terminal amide A'', as defined
above, this is selected from formula V, VI, VII or VIII.
Representative values for formula VI, especially when A' is of
formula II, IV or a bicyclic ring system, include those of the
formula:
##STR00015##
Favoured compounds according to this embodiment include compounds
according to formulae VIa and VIb:
##STR00016##
Further favoured compounds according to this embodiment include
compounds according to formulae VIc and VId:
##STR00017##
Specially preferred compounds according to formula VIa, VIb, VIc
and VId are those wherein n is 1, R.sup.1 is phenyl and/or L is
OH.
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
WO99/48885 and WO94/05639.
Conveniently A'' is of formula V, thus defining a compound of the
formula:
##STR00018##
As recited above, R.sup.8 is H; or R.sup.8 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-.sub.3alkanediylheterocyclyl, any which is optionally
substituted with up to three substituents independently selected
from R.sup.11. Conveniently R.sup.8 is H, optionally substituted
C.sub.1-C.sub.6Alk or optionally substituted
C.sub.0-C.sub.3alkanediylcarbocyclyl. Currently favoured values for
R.sup.8 include H or optionally substituted C.sub.1-C.sub.6Alk,
especially i-propyl or t-butyl.
R.sup.8 is optionally substituted with 1 to 3 members independently
selected from R.sup.11. Representative optional substituents
include oxo, cyano, C.sub.1-C.sub.3Alk or especially halo or
Y--O--Ra, where Y is a bond or C.sub.1-C.sub.3Alk and Ra is H or
C.sub.1-C.sub.3Alk.
As recited above, R.sup.9 is C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-3alkanediylheterocyclyl, any of which is optionally
substituted with up to three substituents independently selected
from R.sup.10; and W is a bond, --NH-- or --O--. Conveniently,
R.sup.9 is optionally substituted C.sub.1-C.sub.6Alk or
C.sub.0-C.sub.3alkanediylcarbocyclyl, especially optionally
substituted methyl, or unsubstituted methyl.
Representative optional substituents to R.sup.9 include halo, oxo,
cyano, azido, nitro, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl, Y--NRaRb or Y--O--Rb where Y
is a bond or C.sub.1-C.sub.3Alk, Ra is H or C.sub.1-C.sub.3Alk and
Rb is H or C.sub.1-C.sub.6Alk, C.sub.0-C.sub.3alkanediylcarbocyclyl
or C.sub.0-C.sub.3alkanediylheterocyclyl. Particularly preferred
optional substituents, for example when R.sup.9 is methyl include
halo, oxo, C.sub.1-C.sub.6Alk,
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl or Y--O--Rb.
When A'' is of formula V, it is currently preferred that W is
--O--.
Formula V may comprise the S or R stereochemistry at the chiral
centre to which R.sup.8 is attached, or a racemate thereof, but it
is currently preferred that it has the stereochemistry shown in the
partial structure:
##STR00019##
One embodiment when A'' is according to formula V includes
compounds wherein R.sup.9 is an optionally substituted heterocyclyl
either directly bonded to W, (i.e. C.sub.0) or bonded to W via an
C.sub.1-C.sub.3alkanediyl chain for example a methylene chain (i.e.
C.sub.1).
Preferred compounds according to this embodiment include those
having the structure according to formulae Va and Vb:
##STR00020##
Specially preferred compounds according to formulae Va and Vb are
those wherein n is 1, R.sup.1 is phenyl and/or L is OH.
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
WO98/00410 and WO96/039398.
Another embodiment when A'' is according to formula V includes
compounds wherein W is a bond and R.sup.9 is
C.sub.0-C.sub.3alkanediylcarbocyclyl or
C.sub.0-C.sub.3alkanediylheterocyclyl, the carbocyclyl and
heterocyclyl being optionally substituted.
Preferred compounds according to this embodiment include those
having the structure according to formulae Vc and Vd:
##STR00021##
Specially preferred compounds according to formula Vc and Vd are
those wherein n is 1, R.sup.1 phenyl and/or L is OH
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
U.S. Pat. No. 5,196,438.
When A'' is of formula VII, it is currently preferred that R.sup.8
is as described above and R.sup.9 is C.sub.1-C.sub.6Alk such as
methyl.
Conveniently A'' is of formula VIII, thus defining compounds of
formula VIIIa:
##STR00022##
As recited above, R.sup.15 is carbocyclyl or heterocyclyl, any of
which is optionally substituted with up to three substituents
independently selected from C.sub.1-C.sub.3Alk, hydroxy, oxo, halo,
Q is O, NR.sup.8 or a bond and r and q are independently 0 or
1.
Representative values for R.sup.15 are 5 to 6 membered, optionally
substituted, aromatic rings containing 0 to 2 heteroatoms, the
heteroatoms being independently selected from N, O and S.
Convenient optional substituents to R.sup.15 include
C.sub.1-C.sub.3Alk, such as methyl, ethyl, propyl or isopropyl.
Representative compounds in this embodiment of the invention are
those wherein Q is a bond and r and q are both zero.
Preferred compounds according to this embodiment are those with the
structures according to formulae VIIIb and VIIIc:
##STR00023##
Specially preferred compounds according to formula VIIIb and VIIIc
are those wherein n is 1, R.sup.1 is phenyl and/or L is OH.
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
U.S. Pat. No. 5,484,926 and U.S. Pat. No. 5,952,343.
Further favoured compounds wherein A'' is according to formula VIII
are those wherein Q is O.
Preferred compounds according to this embodiment include those
having the structures according to formulae VIIId, VIIIe, VIIIf and
VIIIg:
##STR00024##
Specially preferred compounds according to formula VIIId, VIIIe,
VIIIf and VIIIg are those wherein n is 1, R.sup.1 is phenyl and/or
L is OH.
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
WO98/00410 and WO96/39398.
Further favoured compounds wherein A'' is according to formula VIII
are those wherein Q is CR.sup.8.
Preferred compounds according to this embodiment include those
having the structure according to formulae VIIIh and VIIIi:
##STR00025##
Specially preferred compounds according to formula VIIIh and VIIIi
are those wherein n is 1, R.sup.1 is phenyl and/or L is OH.
Suitable building blocks for the preparation of compounds according
to this embodiment of the invention are described herein and in
U.S. Pat. No. 6,372,905 and WO97/21685.
Convenient intermediates specially useful for the synthesis of
compounds of formula (I) wherein n is 0, include epoxides having
the general structure depicted below:
##STR00026## wherein A' and R.sup.1 are as defined above.
Further intermediates, specially useful for the synthesis of
compounds of formula (I) wherein n is 1, include epoxides and
alcohols having the structures shown below:
##STR00027## wherein R.sup.1 is as defined above.
`C.sub.0-C.sub.3alkanediyl-O--C.sub.1-C.sub.3alkyl` as applied
herein is meant to include C.sub.1-C.sub.3alkoxy groups such as
methoxy, ethoxy, n-propoxy, isopropoxy directly bonded (i.e.
C.sub.0) or through an intermediate methylene, ethanediyl,
1,3-propanediyl or 1,3-propanediyl chain.
`C.sub.1-C.sub.6Alk` as applied herein is meant to include straight
and branched aliphatic carbon chain substituents containing from 1
to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, t-butyl, pentyl, isopentyl and hexyl and any
simple isomers thereof. The Alk group may have an unsaturated bond.
Additionally, any C atom in C.sub.1-C.sub.6Alk may optionally be
substituted by one, two or where valence permits three halogens
and/or a heteroatom S, O, NH. If the heteroatom is located at a
chain terminus then it is appropriately substituted with one or 2
hydrogen atoms, such as OH or NH.sub.2. Preferably the
C.sub.1-C.sub.6Alk is small, saturated and unsubstituted or
substituted with halo such as fluoro. C.sub.1-C.sub.4Alk and
C.sub.1-C.sub.5Alk have the corresponding meaning to
C.sub.1-C.sub.6Alk adjusted as necessary for the carbon number. Me
denotes a methyl group.
`C.sub.1-C.sub.3Alk` as applied herein is meant to include methyl,
ethyl, propyl, isopropyl, cyclopropyl, any of which may be
optionally substituted as described in the paragraph above or in
the case of C.sub.2 or C.sub.3, bear an unsaturated bond such as
CH.dbd.CH.sub.2.
`C.sub.0-C.sub.3alkanediyl` as applied herein is meant to include
bivalent straight and branched aliphatic carbon chains such as
methylene, ethanediyl, 1,3-propanediyl, 1,2-propanediyl.
`Amino` includes NH.sub.2, NHC.sub.1-C.sub.3Alk or
N(C.sub.1-C.sub.3Alk).sub.2.
`Halo` or halogen as applied herein is meant to include F, Cl, Br,
I, particularly chloro and preferably fluoro.
`C.sub.0-C.sub.3alkanediylaryl` as applied herein is meant to
include a phenyl, naphthyl or phenyl fused to
C.sub.3-C.sub.7cyclopropyl such as indanyl, which aryl is directly
bonded (i.e. C.sub.0) or through an intermediate methylene,
ethanediylyl, 1,2-propanediyl, or 1,3-propanediyl group as defined
for C.sub.0-C.sub.3alkanediyl above. Unless otherwise indicated the
aryl and/or its fused cycloalkyl moiety is optionally substituted
with 1-3 substituents selected from halo, hydroxy, nitro, cyano,
carboxy, C.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkoxy-C.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkanoyl,
amino, azido, oxo, mercapto, nitro
C.sub.0-C.sub.3alkanediylcarbocyclyl,
C.sub.0-C.sub.3alkanediylheterocyclyl. "Aryl" has the corresponding
meaning.
`C.sub.0-C.sub.3alkanediylcarbocyclyl` as applied herein is meant
to include C.sub.0-C.sub.3alkanediylaryl and
C.sub.0-C.sub.3alkanediylC.sub.3-C.sub.7cycloalkyl. Unless
otherwise indicated the aryl or cycloalkyl group is optionally
substituted with 1-3 substituents selected from halo, hydroxy,
nitro, cyano, carboxy, C.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkanoyl,
amino, azido, oxo, mercapto, nitro,
C.sub.0-C.sub.3alkanediylcarbocyclyl and/or
C.sub.0-C.sub.3alkanediylheterocyclyl. "Carbocyclyl" has the
corresponding meaning, i.e. where the C.sub.0-C.sub.3alkanediyl
linkage is absent
`C.sub.0-C.sub.3alkanediylheterocycylyl` as applied herein is meant
to include a monocyclic, saturated or unsaturated,
heteroatom-containing ring such as piperidinyl, morpholinyl,
piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
thiazinolyl, isothiazinolyl, thiazolyl, oxadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furanyl, thienyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, or any of
such groups fused to a phenyl ring, such as quinolinyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl,
benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl,
benzo-1,2,3-triazolyl, benzo-1,2,4-triazolyl, benzotetrazolyl,
benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl,
benzopyridazinyl, benzopyrazinyl, benzopyrazolyl etc, which ring is
bonded directly i.e. (C.sub.0), or through an intermediate methyl,
ethyl, propyl, or isopropyl group as defined for
C.sub.0-C.sub.3alkanediyl above. Any such non-saturated rings
having an aromatic character may be referred to as heteroaryl
herein. Unless otherwise indicated the hetero ring and/or its fused
phenyl moiety is optionally substituted with 1-3 substituents
selected from halo, hydroxy, nitro, cyano, carboxy,
C.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.6Alk, C.sub.1-C.sub.6alkanoyl,
amino, azido, oxo, mercapto, nitro, C.sub.0-C.sub.3-carbocyclyl,
C.sub.0-C.sub.3heterocyclyl. "Heterocyclyl" and "Heteroaryl" has
the corresponding meaning, i.e. where the C.sub.0-C.sub.3alkanediyl
linkage is absent.
Typically the terms `optionally substituted
C.sub.0-C.sub.3alkanediylcarbocyclyl` and `optionally substituted
C.sub.0-C.sub.3alkanediylheterocyclyl` refers preferably to
substitution of the carbocyclic or heterocyclic ring.
Typically heterocyclyl and carbocyclyl groups are thus a monocyclic
ring with 5 or especially 6 ring atoms, or a bicyclic ring
structure comprising a 6 membered ring fused to a 4, 5 or 6
membered ring.
Typical such groups include C.sub.3-C.sub.8cycloalkyl, phenyl,
benzyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl such as
from azepanyl, azocanyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, indolinyl, pyranyl,
tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl,
tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, tetrazolyl, pyrazolyl, indolyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,
benzisoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl and
quinoxalinyl, any of which may be optionally substituted as defined
herein.
The saturated heterocycle thus includes radicals such as
pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,
indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl,
1,4,5,6-tetrahydropyrimidinylamine, dihydro-oxazolyl,
1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,
isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione, whereas
the unsaturated heterocycle include radicals with an aromatic
character such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl. In each
case the heterocycle may be condensed with a phenyl ring to form a
bicyclic ring system.
The compounds of the invention can form salts which form an
additional aspect of the invention. Appropriate pharmaceutically
acceptable salts of the compounds of Formula I include salts of
organic acids, especially carboxylic acids, including but not
limited to acetate, trifluoroacetate, lactate, gluconate, citrate,
tartrate, maleate, malate, pantothenate, isethionate, adipate,
alginate, aspartate, benzoate, butyrate, digluconate,
cyclopentanate, glucoheptanate, glycerophosphate, oxalate,
heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate,
3-phenylpropionate, picrate, pivalate, proprionate, tartrate,
lactobionate, pivolate, camphorate, undecanoate and succinate,
organic sulphonic acids such as methanesulphonate,
ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate,
2-napthalenesulphonate, benzenesulphonate,
p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic
acids such as hydrochloride, hydrobromide, hydroiodide, sulphate,
bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and
sulphonic acids. The compounds of Formula I may in some cases be
isolated as the hydrate.
It will be appreciated that the invention extends to prodrugs,
solvates, complexes and other forms releasing a compound of formula
I in vivo.
While it is possible for the active agent to be administered alone,
it is preferable to present it as part of a pharmaceutical
formulation. Such a formulation will comprise the above defined
active agent together with one or more acceptable
carriers/excipients and optionally other therapeutic ingredients.
The carrier(s) must be acceptable in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient.
The formulations include those suitable for rectal, nasal, topical
(including buccal and sublingual), vaginal or parenteral (including
subcutaneous, intramuscular, intravenous and intradermal)
administration, but preferably the formulation is an orally
administered formulation. The formulations may conveniently be
presented in unit dosage form, e.g. tablets and sustained release
capsules, and may be prepared by any methods well known in the art
of pharmacy.
Such methods include the step of bringing into association the
above defined active agent with the carrier. In general, the
formulations are prepared by uniformly and intimately bringing into
association the active agent with liquid carriers or finely divided
solid carriers or both, and then if necessary shaping the product.
The invention extends to methods for preparing a pharmaceutical
composition comprising bringing a compound of Formula I or its
pharmaceutically acceptable salt in conjunction or association with
a pharmaceutically acceptable carrier or vehicle. If the
manufacture of pharmaceutical formulations involves intimate mixing
of pharmaceutical excipients and the active ingredient in salt
form, then it is often preferred to use excipients which are
non-basic in nature, i.e. either acidic or neutral.
Formulations for oral administration in the present invention may
be presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active agent; as a
powder or granules; as a solution or a suspension of the active
agent in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water in oil liquid emulsion and
as a bolus etc.
With regard to compositions for oral administration (e.g. tablets
and capsules), the term suitable carrier includes vehicles such as
common excipients e.g. binding agents, for example syrup, acacia,
gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone),
methylcellulose, ethylcellulose, sodium carboxymethylcellulose,
hydroxypropylmethylcellulose, sucrose and starch; fillers and
carriers, for example corn starch, gelatin, lactose, sucrose,
microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate,
sodium chloride and alginic acid; and lubricants such as magnesium
stearate, sodium stearate and other metallic stearates, glycerol
stearate stearic acid, silicone fluid, talc waxes, oils and
colloidal silica. Flavouring agents such as peppermint, oil of
wintergreen, cherry flavouring or the like can also be used. It may
be desirable to add a colouring agent to make the dosage form
readily identifiable. Tablets may also be coated by methods well
known in the art.
A tablet may be made by compression or moulding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active agent in a
free flowing form such as a powder or granules, optionally mixed
with a binder, lubricant, inert diluent, preservative,
surface-active or dispersing agent. Moulded tablets may be made by
moulding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may be
optionally be coated or scored and may be formulated so as to
provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include
lozenges comprising the active agent in a flavoured base, usually
sucrose and acacia or tragacanth; pastilles comprising the active
agent in an inert base such as gelatin and glycerin, or sucrose and
acacia; and mouthwashes comprising the active agent in a suitable
liquid carrier.
The appropriate dosage will depend upon the indications and the
patient, and is readily determined by conventional animal drug
metabolism and pharmacokinetics (DMPK) or clinical trials and in
silico prediction software.
In treating HIV, the compounds of formula I are typically
administered in an amount to achieve a plasma level of around 100
to 5000 nM, such as 300 to 2000 nM. This corresponds to a dosage
rate, depending on the bioavailability of the formulation, of the
order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A
typical dosage rate for a normal adult will be around 0.05 to 5 g
per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four
dosage units per day. As with all pharmaceuticals, dosage rates
will vary with the size and metabolic condition of the patient as
well as the severity of the infection and may need to be adjusted
for concomitant medications.
In general dosages of from about 3 mg to approximately 1.6 grams
per person per day, divided into 1 to 3 single doses, are suitable.
A typical dosage for adult patients is 50-800, more preferably
400-600 twice, or most preferably once daily. As elaborated below
HIV inhibitors are typically co-administered in a unit dosage form
with other HIV inhibitors or metabolism modifying agents and the
dosage regime (QQ, BiD TiD, fast/with food etc) for such
co-administered drugs will of course necessitate concomitant
adjustment of the dosage regime for formula I
As is good prescribing practice with antiviral therapy, the
compounds of formula I are typically co-administered with other HCV
therapies to avoid the generation of drug escape mutants. However,
certain antifectives can induce a synergistic response, allowing
one or both of the active ingredients to be administered at a lower
dose that the corresponding monotherapy. For example in drugs prone
to rapid metabolism by Cyp3A4, co-dosing with the HIV protease
inhibitor ritonavir can allow lower dosage regimes to be
administered. The compound of the invention and the or each further
antiviral agent are typically co-administered at molar ratios
reflecting their respective activities and bioavailabilities.
Generally such ratio will be of the order of 25:1 to 1:25, relative
to the compound of formula I, but may be lower, for instance in the
case of cytochrome antagonists such as ritonavir.
Representative HIV antivirals include NRTI such as alovudine (FLT),
zudovudine (AZT, ZDV), stavudine (d4T, Zerit), zalcitabine (ddC),
didanosine (ddI, Videx), abacavir, (ABC, Ziagen), lamivudine (3TC,
Epivir), emtricitabine (FTC, Emtriva), racevir (racemic FTC),
adefovir (ADV), entacavir (BMS 200475), alovudine (FLT), tenofovir
disoproxil fumarate (TNF, Viread), amdoxavir (DAPD), D-d4FC
(DPC-817), -dOTC (Shire SPD754), elvucitabine (Achillion
ACH-126443), BCH 10681 (Shire), SPD-756, racivir, MIV-606
(Medivir), D-FDOC, GS7340, INK-20 (thioether phospholipid AZT,
Kucera), 2'3'-dideoxy-3'-fluoroguanosine (FLG) & its prodrugs
such as MIV-210, reverset (RVT, D-D4FC, Pharmasset DPC-817).
Representative NNRTI include delavirdine (Rescriptor), efavirenz
(DMP-266, Sustiva), nevirapine (BIRG-587, Viramune), (+)calanolide
A and B (Advanced Life Sciences), capravirine (AG1549f S-1153;
Pfizer), GW-695634 (GW-8248; GSK), MIV-150 (Medivir), MV026048
(R-1495; Medivir AB/Roche), NV-05 2 2 (Idenix Pharm.), R-278474
(Johnson & Johnson), RS-1588 (Idenix Pharm.), TMC-120/125
(Johnson & Johnson), TMC-125 (R-165335; Johnson & Johnson),
UC-781 (Biosyn Inc.) and YM215389 (Yamanoushi).
Representative HIV protease inhibitors include PA-457 (Panacos),
KPC-2 (Kucera Pharm.), 5 HGTV-43 (Enzo Biochem), amprenavir
(VX-478, Agenerase), atazanavir (Reyataz), indinavir sulfate
(MK-639, Crixivan), Lexiva (fosamprenavir calcium, GW-433908 or
908, VX-175), ritonavir (Norvir), lopinavir+ritonavir (ABT-378,
Kaletra), tipranavir, nelfinavir mesylate (Viracept), saquinavir
(Invirase, Fortovase), AG1776 (JE-2147, KNI-764; Nippon Mining
Holdings), AG-1859 (Pfizer), DPC-681/684 (BMS), GS224338 (Gilead
Sciences), KNI-272 (Nippon Mining Holdings), Nar-DG-35 (Narhex),
P(PL)-100 (P-1946; Procyon Biopharma), P-1946 (Procyon Biopharma),
R-944 (Hoffmann-LaRoche), RO-0334649 (Hoffmann-LaRoche), TMC-114
(Johnson & Johnson), VX-385 (GW640385; GSK/Vertex), VX-478
(Vertex/GSK).
Other HIV antivirals include entry inhibitors, including fusion
inhibitors, inhibitors of the CD4 receptor, inhibitors of the CCR5
co-receptor and inhibitors of the CXCR4 coreceptor, or a
pharmaceutically acceptable salt or prodrug thereof. Examples of
entry inhibitors are AMD-070 (AMD 11070; AnorMed), BlockAide/CR
(ADVENTRX Pharm.), BMS 806 (BMS-378806; BMS), Enfurvirtide (T-20,
R698, Fuzeon), KRH1636 (Kureha Pharmaceuticals), ONO-4128
(GW-873140, AK-602, E-913; ONO Pharmaceuticals), PRO-140 (Progenics
Pharm), PRO-542 (Progenics Pharm.), SCH-D (SCH-417690;
Schering-Plough), T-1249 (R724; Roche/Trimeris), TAK-220 (Takeda
Chem. Ind.), TNX-355 (Tanox) and UK-427,857 (Pfizer). Examples of
integrase inhibitors are L-870810 (Merck & Co.), c-2507 (Merck
& Co.) and S(RSC)-1838 (shionogi/GSK).
Many HIV patients are co-infected, or prone to superinfection, with
other infectious diseases. Accordingly, a further aspect of the
invention provides combination therapies comprising the compound of
the invention co-formulated in the same dosage unit or co-packaged
with at least one further anti-infective pharmaceutical. The
compound of the invention and the at least one further antinfective
are administered simultaneously or sequentially, typically at doses
corresponding to the monotherapy dose for the agent concerned.
Typical coinfections or superinfections include hepatitis B virus
(HBV) or Hepatitis C virus (HCV). Accordingly the compound of the
invention is advantageously co-administered (either in the same
dosage unit, co-packaged or separately prescribed dosage unit) with
at least one HCV antiviral and/or at least one HBV antiviral.
Accordingly the compound of the invention is advantageously
co-administered (either in the same dosage unit, co-packaged or
separately prescribed dosage unit) with at least one HCV antiviral
and/or at least one HBV antiviral.
Examples of HBV antivirals include lamivudine and
2'3'-dideoxy-3'-fluoroguanosine (FLG) & its prodrugs such as
the 5'-O-lacytlvalyl prodrug MIV-210. These HBV antivirals are
particularly convenient as they are simultaneously active against
both HBV and HIV.
Examples of HCV antiviral for co-administration with formula I
include immune modifiers such as ribavirin or interferons,
nucleoside HCV polymerase inhibitors or HCV protease inhibitors,
many of which are currently under development.
The compounds of the invention are believed to counteract elevated
LDL-cholesterol and/or triglyceride levels often appearing as a
side effect of prior art HIV protease inhibitors. Accordingly the
compounds of the invention are useful for replacing such prior art
inhibitors in the ongoing dosage regimes of patients. Typically
such patient has been or is undergoing antiretroviral therapy with
one or more conventional HIV protease inhibitors and exhibits
elevated plasma LDL-cholesterol and/or triglyceride levels. Such
other HIV protease inhibitor(s) may be given as monotherapy or as
part of an antiretroviral therapy which also includes one or more
other antiretroviral drugs such as reverse transcriptase inhibitors
or nonnucleoside reverse transcriptase inhibitors. Such candidates,
although they may exhibit satisfactory viral suppression, may be of
increased risk for hyperlipidemia and premature cardiovascular
events.
The term "elevated plasma LDL-cholesterol and triglyceride levels"
as used herein is based on the National Cholesterol Education
Program (NCEP) clinical practice guidelines for the prevention and
management of high cholesterol in adults.
In the latest guidelines issued in 2001, plasma levels of >130
mg/dL of LDLcholesterol and >150 mg/dL of triglycerides are
considered elevated or "high". The process of the present invention
is particularly useful for those patients having plasma
triglyceride levels of >200 mg/dL and for those patients with no
risk factors or previous cardiovascular events having
LDL-cholesterol levels of >160 mg/dL.
The definition of "elevated" LDL-cholesterol and triglyceride
levels may, of course, change in the future as the NCEP continues
to evaluate heart attack risk factors. It is intended, then, that
the term "elevated LDL-cholesterol and triglyceride levels" as used
will be consistent with current NCEP guidelines.
In one of its aspects, the present invention involves discontinuing
the offending (the drug responsible for the elevated plasma
LDL-cholesterol and/or triglyceride levels) HIV protease inhibitor
from the above regimen and substituting therefore an amount of the
compound of formula I which is effective to inhibit HIV and to
reduce plasma LDL-cholesterol and/or triglyceride levels.
The dose of the compound of the invention to be employed depends on
such factors as the body weight, age and individual condition of
the patient to be treated and the mode of administration.
It is believed that the compounds according to some embodiments of
the invention can in certain formulations interact favourably with
cytochrome P450 monooxygenase and can improve the pharmacokinetics
of drugs metabolized by this enzyme, including particularly other
HIV protease inhibitors such as saquinavir, indinavir, nelfinavir,
araprenavir, tipanavir and lopinavir. Thus, it may act in a similar
way to ritonavir described in U.S. Pat. No. 6,037,157 to increase
blood levels of the coadministered HIV protease inhibitor.
Conveniently and in contradistinction to ritonavir it is believed
that the compound of the invention may be employed in combination
therapy with other HIV protease inhibitors at its normal
therapeutic dose level instead of the sub-therapeutic dose levels
used with ritonavir. Any such potentiating effect on other HIV
protease inhibitors which are metabolized by cytochrome P450
monooxygenase, may allow the use of the compounds of the invention
concomitantly with such other HIV protease inhibitors thereby
allowing reduced dosages of such other HIV protease inhibitors to
be used while maintaining the same degree of viral suppression.
Conceivably the compound of the invention can be used in
combination with other HIV protease inhibitors to reduce
LDL-cholesterol and triglyceride levels in AIDS patients undergoing
protease inhibitor therapy while still maintaining the desired
level of viral suppression.
The appropriate dose of the HIV protease inhibitor being combined
with the compounds of the invention can be determined by the
following method which was used for the atazanavir/saquinavir
combination, as disclosed in WO03020206. Atazanavir is a moderate
inhibitor of the cytochrome P450 3A enzyme comparable to nelfinavir
and indinavir, with a Ki of 2.4 .mu.M. The latter two compounds
increase the exposure of saquinavir (dosed at 1200 mg thrice-daily
(TID) by 392 and 364%, respectively, at steady-state. A
multiple-dose pharmacology study was completed to evaluate if a
similar increase could be expected for the combination of
atazanavir and saquinavir. This study showed a greater than 3-fold
increase in exposure, due to combination with atazanavir,
supporting a 1200 mg once-daily saquinavir dosing, was equivalent
to the currently marketed saquinavir regimen of 1200 mg TID. Using
a constant dose of atazanavir the range of saquinavir doses were
studied to target the saquinavir exposure (AUC (area under the
curve) and CMIN (minimum concentration)) similar to those in the
literature. Similarly, appropriate dosing of other HIV protease
inhibitors to be used in combination with the compound of the
invention can be calculated.
Compounds of the invention are typically synthesized outlined
below.
A method to prepare compounds according to the present invention
wherein E is N and n is 0 is by reacting a suitable epoxide with a
desired hydrazide derivative as illustrated in scheme 1.
##STR00028##
A suitable derivative of malonic acid (1a) where R.sup.1 is as
described above, can be transformed into an acrylic acid derivative
(1b) by way of a Mannich reaction followed by in situ
decarboxylation. Various derivatives of malonic acid are available
commercially or they are easily prepared by the skilled person
according to literature procedures. The acrylic acid can then be
coupled to a desired amine A'-NH.sub.2, where A' is as defined
above, using standard peptide coupling conditions for example by
using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDAC), N-methylmorpholine (NMM) and 1-hydroxybenzotriazole (HOBT)
or any other suitable conditions that are known by the skilled
person, to give the acrylamide derivative (1c). Epoxidation of the
double bond by any suitable method like using a peroxide for
instance 3-chloroperoxybenzoic acid (mCPBA) provides the
corresponding epoxide (1d). Subsequent opening of the formed
epoxide by a suitable hydrazide (1e) optionally in the presence of
titanium(IV) isopropoxide as described in JOC, 50, 1985 p. 1557
yields the tertiary alcohol (1f). If desired, the afforded hydroxy
group can then be converted to a fluoride or a primary or secondary
amine thus providing compounds according to general formula I
wherein n is 0, X is H, E is N and L is F, NHC.sub.1-C.sub.3alkyl
or N(C.sub.1-C.sub.3alkyl).sub.2, as shown in scheme 2 below.
##STR00029##
Reaction of the alcohol (1f) with a suitable fluorinating agent
such as DAST or Deoxofluor or the like in a solvent like
dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M.
in Synthesis, 17, 1999, p. 2561-2578, yields the corresponding
fluoro compound (2a). Alternatively, the hydroxy group of the
alcohol (1f) can be transferred to an amine using any convenient
method described in the literature. For example the Mitsunobu
procedure can be used, i.e. reaction of the alcohol (1f) with an
azodicarboxylate such as DIAD or the like in the presence of
triphenylphosphine followed by displacement with a desired amine to
provide the corresponding amino derivative (2b). An alternative
route to the amine (2b) is by transformation of the hydroxy group
into a leaving group such as a derivative of sulphonic acid like a
mesylate, triflate, tosylate or the like by treatment with the
appropriate sulphonylating agent in a solvent like for instance
pyridine or dichloromethane optionally in the presence of
triethylamine or the like, followed by displacement of the leaving
group with a desired primary or secondary amine
NH.sub.2C.sub.1-C.sub.3alkyl or NH(C.sub.1-C.sub.3alkyl).sub.2.
Alternatively, the leaving group can be displaced with azide, or
the hydroxy group can be converted directly to an azide by use of
an azide transfer agent like diphenyl phosphoryl azide (DPPA),
subsequent reduction of the introduced azide to an amine, by for
example triphenylphosphine optionally in the presence of a base
like triethylamine provides compounds wherein L is NH.sub.2 whereas
a reductive amination of the afforded amine with a desired aldehyde
or ketone provides secondary or tertiary amines.
The above described intermediates, for example the epoxide 1d,
wherein A' and R.sup.1 are as defined above are novel compounds and
constitute a further aspect of the invention.
Various amines, A'-NH.sub.2, used in scheme 1 are available
commercially or alternatively they can be prepared according to
literature procedures. For example, amines wherein A' is according
to formula (IV) can be prepared as described by B. Samuelsson et
al. in Bioorg. Med. Chem., 11, 2003, p. 1107-1115. Alternatively,
they can be prepared from the corresponding alcohols A'-OH by
transforming the hydroxy group to an amino group. This
transformation can be effected by any suitable method known by the
skilled person, for instance by converting the hydroxy group to a
leaving group such as a halide like a bromide, chloride or iodide
or to a derivative of sulphonic acid such as a mesylate, triflate
or tosylate, followed by a nucleophilic displacement reaction with
azide and finally reduction of the azide to the amine using any
suitable reduction method such as catalytic hydrogenation. Suitable
alcohols are described for example by A. K. Gosh et al. in J. Med.
Chem., 1996, 39, 3278-3290.
A further alternative to prepare amines, A'-NH.sub.2, wherein A' is
according to formula (IV) is illustrated in scheme 3.
##STR00030##
Addition of a bromide and a propargyloxy group to the double bond
of the unsaturated ring (3a) effected for instance by reaction with
N-bromosuccinimide and propargyl alcohol followed by a reductive
ring closure reaction promoted by tri-n-butyltin hydride in the
presence of a radical initiator for example
1,1'-azobis(isobutyronitrile) or the like yields bicyclic olefin
(3c). The exocyclic double bond can then be cleaved oxidatively by
subjecting the olefinic compound to the appropriate oxidation
conditions such as treatment with osmium tertoxide in combination
with sodium periodate which gives the keto derivative (3d).
Reaction of the formed keto group with O-benzylhydroxylamine
followed by reduction with a reducing agent like lithium aluminium
hydride gives the corresponding amine (3f) as a racemic mixture.
The racemic mixture can thereafter be separated according to
procedures known in the art. For example, a diastereomeric mixture
which can be separated by chromatographic methods, can be prepared
by coupling of a chiral auxiliary compound such as a chiral amino
acid for example Boc-L-phenylalanine, using standard peptide
coupling methods. Separation of the mixture and thereafter cleavage
of the auxiliary amino acid then provides the pure diastereomers of
the desired amine (3f).
An example of the preparation of amine derivatives A'-NH.sub.2 used
i.a. in scheme 1 wherein A' is according to formula (II) is shown
in scheme 4 below.
##STR00031##
Coupling of a suitably N-protected, for example Boc protected,
amino acid (4a), carrying the desired side chain R.sup.3 to an
amino derivative (4b), where R.sup.3 and R.sup.4 are as defined
above, using standard peptide coupling conditions, like using
coupling reagents such as EDAC, NMM and HOBT in an inert solvent
like dimethylformamide gives the amide (2Bc). Removal of the
N-protecting group, by acidic treatment in the case of a Boc
protecting group, for example by using trifluoroacetic acid in
dichloromethane, gives the amine (4d). Amino acids (4a) used in the
above scheme are commercially available or they can be prepared
according to literature procedures. A method to prepare amino acids
carrying a branched side chain is exemplified in Scheme 4A.
##STR00032##
Treatment of the amino acid (4Aa), achieved as described by
Rapoport et al. in J. Org. Chem., 55, (1990) p. 5017-5025, with one
or two successive additions of a base such as potassium
bis-(trimethylsilyl) amide (KHMDS) and methyl iodide provides mono
or dimethylated amino acid (4Ab) respectively. Reduction of the
side chain ester using a reagent like DIBAL followed by
interchanging of the PhFl group for a Boc group effected by
catalytic hydrogenation in the presence of Boc.sub.2O and a
catalyst like Pd/C, provides the alcohol (4Ac). If desired, the
hydroxy group of the afforded alcohol can subsequently be
methylated for instance by treatment with a suitable methylating
agent such as methyl iodide and a base like NaH which gives the
methoxy compound (4Ae). Alternatively, the alcohol can be converted
to the corresponding fluorocompound (4Ad) by treatment with a
fluorinating agent such as DAST or the like, or any other suitable
fluorinating method described herein or elsewhere can be used.
Amines, A'-NH.sub.2, wherein A' is according to formula (III) can
be prepared as exemplified in scheme 5.
##STR00033##
Reaction of a natural or non-natural amino acid (5a) carrying the
appropriate side chain R.sup.3 defined as above, with a desired
acylating agent; a chloroformate (i) for the formation of compounds
wherein W is O, an acid chloride (ii) for the formation of
compounds wherein W is a bond or an isocyanate (iii) for the
formation of compounds wherein W is NH, provides the acid (5b). The
amine A'-NH.sub.2 (5d) can then be achieved by transforming the
acid (5b) to the corresponding primary amide (5c) for example by
treatment with an ammonia solution in the presence of isobutyl
chloroformate and N-methylmorpholine in a solvent like dimethoxy
ethane, followed by a rearrangement reaction brought about by
treatment with [bis(trifluoroacetoxy)iodo]benzene optionally in the
presence of pyridine as described e.g. by J-A. Fehreentz in J. Med.
Chem., 2003, 46, 1191-1203.
Hydrazide derivatives (1e) used in scheme 1 can be prepared by
reaction of an acid A''COOH or a derivative thereof, for instance
an acid chloride or an acid anhydride, with a hydrazine
R.sup.2CH.sub.2NHNH.sub.2 under standard peptide coupling
conditions. Scheme 6 shows an example wherein A'' in the acid,
A''COOH is according to formula (V) as defined above.
##STR00034##
Reaction of a natural or non-natural amino acid (6a) carrying the
appropriate side chain R.sup.8 defined as above, with a desired
acylating agent as described in scheme 3 provides the acid (6b).
The hydrazide derivative (6d) can then be achieved by coupling of a
hydrazine derivative (6c) which is available either commercially or
in the literature, using standard peptide coupling conditions as
described above.
Compounds wherein A'' is according to formula (VII) can
conveniently be prepared according to the above described route but
with the use of a suitable sulphonylating agent like alkylsulphonyl
chloride, R.sup.9--S(.dbd.O).sub.2Cl, in the presence of a base
like sodium hydroxide, instead of any of the depicted acylating
agents i, ii or iii, in the reaction with amino acid 3a.
Hydrazides (1e) wherein A'' is according to formula (VI) can be
prepared by reaction of an appropriate electrophilic carbonyl
compound such as a chloroformate or an activated carbonate with the
hydrazine derivative R.sup.2CH.sub.2NHNH.sub.2 as illustrated in
scheme 7.
##STR00035##
The alcohol (7a) can be converted to the corresponding activated
carbonate (7b) or chloroformate by reaction of the hydroxy group
with a suitable acylating agent like a carbonate such as dipyridyl
carbonate or para-nitrophenyl chloroformate optionally in the
presence of a base such as triethylamine or imidazole, or to a
chloroformate by reaction with phosgene optionally in the presence
of base like sodium hydrogen carbonate. The afforded electrophilic
compound can then be reacted with a desired hydrazine derivative
(7c) to give the corresponding hydrazide (7d). Alcohol (7a) is
either commercially available or can be prepared for example as
described by A. K. Ghosh et al. in J. Med. Chem., 1996, 39,
3278-3290.
The procedure described in scheme 7 can also be applied to other
alcohols for instance optionally substituted carbocyclylmethanol,
optionally substituted heterocyclylmethanol, optionally substituted
carbocycloalcohol or optionally substituted heterocyclalcohol thus
providing hydrazides wherein A'' is according to formula (VIII) as
defined above.
A route to compounds according to general formula I wherein E is N
and n is 1 is depicted in scheme 8.
##STR00036##
Condensation of .gamma.-butyrolactone (8a) with a suitable aldehyde
(8b) in the presence of a base like potassium t-butoxide in an
inert solvent like benzene, dichloromethane or the like provides
the olefinic compound (8c). Epoxidation of the double bond can then
be effected for example by using mCPBA in the presence of a
catalytic amount of a radical initiator such as AIBN or the like
which gives the epoxide (8d). Reductive opening of the epoxide by
for instance catalytic hydrogenation in the presence of a catalyst
like Pt(IV)O or the like, followed by ring opening of the lactone
with a desired amine, A'-NH.sub.2, gives the diol (8f). Oxidation
of the primary alcohol by any suitable oxidation method like for
example using Dess-Martin periodinate provides the aldehyde (8 g)
which subsequently can be reacted with a suitable hydrazide
derivative (8 h) in a reductive amination reaction, using a
reduction agent like NaCNBH.sub.4, to give the hydrazide (8i). The
N-substituent CH.sub.2--R.sup.2 can then be introduced by
alkylation of the .beta.-nitrogen of the hydrazide with a desired
alkylating agent (8j) wherein R.sup.2 is as defined above and X is
a leaving group such as a halide like chloride, bromide or iodide
or a derivative of sulphonic acid such as a triflate, mesylate or
tosylate, thus providing the N-alkylated compound (8k). The above
synthetic route can also be carried out starting from
.beta.-propiolactone thus giving compounds of general formula I
wherein n is 0. The N-alkylated hydrazide (8k) can also be prepared
more directly by reacting the aldehyde (8 g) with an already
N-alkylated hydrazine derivative like compound 3d from scheme
3.
The intermediates above, such as the epoxide 8d and alcohol 8e
where R.sup.1 is as defined above are novel compounds and
constitute another aspect of the invention.
If desired the hydroxy group of compound (8k) can be converted to a
fluoride or a primary or secondary amine thus providing compounds
according to general formula I wherein n is 1, X is H, E is N and L
is F, NHC.sub.1-C.sub.3alkyl or N(C.sub.1-C.sub.3alkyl).sub.2, as
shown in scheme 9 below.
##STR00037##
Reaction of alcohol 8k with a suitable fluorinating agent such as
DAST or Deoxofluor or the like in a solvent like dichloromethane as
described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17,
1999, p. 2561-2578, yields the corresponding fluoro compound 9a.
Alternatively, the hydroxy group of compound 8k can be transferred
to an amine using any convenient method described in the
literature. For example the Mitsunobu procedure can be used, i.e.
reaction of the alcohol (8k) with an azodicarboxylate such as DIAD
or the like in the presence of triphenylphosphine followed by
displacement with a desired amine which provides the corresponding
amino derivative (9b). An alternative route to the amine (9b) is by
transformation of the hydroxy group into a leaving group such as a
derivative of sulphonic acid like a mesylate, triflate, tosylate or
the like by treatment with the appropriate sulphonylating agent in
a solvent like for instance pyridine or dichloromethane optionally
in the presence of triethylamine or the like, followed by
displacement of the leaving group with a desired primary or
secondary amine NH.sub.2C.sub.1-C.sub.3alkyl or
NH(C.sub.1-C.sub.3alkyl).sub.2. Alternatively, the leaving group
can be displaced with azide, or the hydroxy group can be converted
directly to an azide by use of an azide transfer agent like
diphenyl phosphoryl azide (DPPA), subsequent reduction of the
introduced azide to an amine, by for example triphenylphosphine
optionally in the presence of a base like triethylamine provides
compounds wherein L is NH.sub.2 whereas a reductive amination of
the afforded amine with a desired aldehyde or ketone provides
secondary or tertiary amines.
Dihydroxylated or difluorinated compounds wherein n is 1, E is N
and X=L=OH or F in general formula I can be prepared as depicted in
scheme 10.
##STR00038##
The olefine derivative (10a) can be achieved from the alcohol (8f),
prepared as described in scheme 8, by transforming the primary
alcohol to a leaving group such as a mesylate or the like followed
by an elimination reaction brought about for example by treatment
with a base such as t.BuOK or DBU in a solvent like DMSO, DMF or
dichloromethane optionally in the presence of a crown ether. The
afforded unsaturated compound (10a) can then be epoxidized by
treatment with a suitable oxidizing reagent such as mCPBA or BuOOK
or the like in a solvent like dichloromethane to give the epoxide
(10b). Opening of the epoxide with a desired hydrazide derivative
as described in scheme 1 then yields the diol (10d). Alternatively,
a dihydroxylation of the double bond in the olefin (10a) can be
performed for example by treatment with an oxidizing system such as
OsO.sub.4 and NMMO or the like which gives the triol (10c).
Transformation of the primary alcohol into a leaving group as
described above followed by a substitution reaction with the
desired hydrazide derivative provides the dihydroxy hydrazide
(10d). If desired, the two hydroxy groups can then be converted to
fluorides by fluorination procedures known in the art for instance
by using a fluorinating reagent such as DAST, Deoxofluor or the
like as described by Rajendra et al. in Synthesis 17, 2002, p.
2561-2578, to give the difluorohydrazide (10e).
Compounds according to general formula I wherein n is 1, E is N, X
is OH and L is F, NH(C.sub.1-C.sub.3alkyl) or
N(C.sub.1-C.sub.3alkyl).sub.2 can be prepared as exemplified in
scheme 11.
##STR00039##
Transformation of the primary alcohol 8f, prepared as described in
scheme 8, to a leaving group such as a derivative of sulphonic acid
like a mesylate, triflate, tosylate or the like by treatment with
the appropriate sulphonylating agent in a solvent like for instance
pyridine or dichloromethane optionally in the presence of
triethylamine or the like, followed by an elimination reaction
brought about for instance by treatment with a base such as t.BuOK
or DBU in a solvent like DMSO, DMF or dichloromethane optionally in
the presence of a crown ether, or any other suitable elimination
conditions. The hydroxy group of the afforded unsaturated compound
(11b) can then be converted to a fluoride for example by reaction
with a suitable fluorinating agent such as DAST or Deoxofluor or
the like in a solvent like dichloromethane as described e.g. by
Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p.
2561-2578, which yields the corresponding fluoro compound (11c).
Alternatively, the hydroxy group of compound (11b) can be
transferred to an amine using any convenient method described in
the literature. For example the Mitsunobu procedure can be used,
i.e. reaction of the alcohol (11b) with an azodicarboxylate such as
DIAD or the like in the presence of triphenylphosphine followed by
displacement with a desired amine which provides the corresponding
amino derivative (11c). An alternative route to the amine (11c) is
by transformation of the hydroxy group into a leaving group such as
a derivative of sulphonic acid like a mesylate, triflate, tosylate
or the like by treatment with the appropriate sulphonylating agent
in a solvent like for instance pyridine or dichloromethane
optionally in the presence of triethylamine or the like, followed
by displacement of the leaving group with a desired primary or
secondary amine NH.sub.2C.sub.1-C.sub.3alkyl or
NH(C.sub.1-C.sub.3alkyl).sub.2. Alternatively, the leaving group
can be displaced with azide, or the hydroxy group can be converted
directly to an azide by use of an azide transfer agent like
diphenyl phosphoryl azide (DPPA), subsequent reduction of the
introduced azide to an amine, by for example triphenylphosphine
optionally in the presence of a base like triethylamine provides
compounds wherein L is NH.sub.2 whereas a reductive amination of
the afforded amine with a desired aldehyde or ketone provides
secondary or tertiary amines.
Further treatment of the olefinic compound (11c) as described for
compound 10a in scheme 10, i.e. either epoxidation of the double
bond followed by reaction with the desired hydrazide derivative or
dihydroxylation of the double bond followed by mesylation,
substitution and finally reaction with the desired hydrazide
derivative, provides the hydrazide derivative (11d). If desired,
the hydroxy group of compound 11d can be converted to a fluoride by
treatment with DAST or the like, as previously described thus
providing compounds according to general formula I wherein X is
F.
A route to compounds according to general formula I wherein n is 1,
E is N, X is F and L is OH, F, NH(C.sub.1-C.sub.3alkyl) or
N(C.sub.1-C.sub.3alkyl).sub.2 is illustrated in scheme 12.
##STR00040##
Opening of the epoxide (10b) by use of a fluorinating agent such as
(HF).sub.x/pyridine as described i.a. by Baklouti, A. et al. in
Synthesis 1999, p. 85-89, or (i-PrO).sub.2TiF.sub.2-ET.sub.4NF-nHF
as described by Hara, S. et al. in Tetrahedron 55, 1999, p.
4947-4954 or any other suitable fluorinating agent provides the
fluorohydrine (12a). Transformation of the primary hydroxy group
into a leaving group such as a derivative of sulphonic acid like a
mesylate, triflate, tosylate or the like by treatment with the
appropriate sulphonylating agent in a solvent like for instance
pyridine or dichloromethane optionally in the presence of
triethylamine or the like, followed by reaction with a desired
hydrazide derivative then gives the hydrazide (12b). If desired,
the hydroxy group of the hydrazide (12b) can be converted to a
fluoride by treatment with DAST or the like thus providing
compounds according to general formula I wherein L is F, or the
hydroxy group can be converted to an amine for example by way of a
Mitsunobu reaction by treatment with the desired amine in the
presence of DIAD or the like or by transformation of the hydroxy
group to an azide followed by reduction of the azide to an amine,
thus providing compound according to general formula I wherein L is
NH.sub.2 or the afforded amine can be reacted in a reductive
amination with a desired aldehyde or ketone as previously
described, thus providing compounds according to general formula I
wherein L a substituted amine.
Compounds according to general formula I wherein L is F, X is
C.sub.1-C.sub.3alkyl, n is 1 and E is N can be prepared as
illustrated in scheme 13.
##STR00041##
Epoxidation of the olefinic compound (11c), prepared as described
in scheme 11, by reaction with a suitable oxidizing agent such as
mCPBA or t.BuOOK or the like in a solvent like dichloromethane
provides epoxide (13a). The alkylated compound (13b) can the be
achieved by regioselective opening of the epoxide effected for
example by using an aluminium reagent such as
(alkyl).sub.2AlOAlalkyl or (alkyl).sub.3Al in the presence of water
in a solvent like dichloromethane as described i.a. by Maruoka, K.
et al. in Tetrahedron Lett., 40, 1999, p. 5369-5372 or by using an
alkyltitanium reagent as described by Tanaka, T. et al. in
Tetrahedron Lett. 45, 2004, p. 75-78. Conversion of the formed
primary alcohol to a leaving group such as a halide like chlorine,
bromine or iodine or to a derivative of sulphonic acid such as a
mesylate, triflate, tosylate or the like by treatment with the
appropriate sulphonylating agent in a solvent like for instance
pyridine or dichloromethane optionally in the presence of
triethylamine or the like, followed by reaction with a desired
hydrazide derivative optionally in the presence of a base like
Et.sub.3N, t.BuOK or the like then gives the hydrazide (13d).
The synthesis of hydrazides (8 h) are described in the literature,
se for example J. Med. Chem. 1998, 41, p. 3387, a general example
thereof is shown in scheme 14.
##STR00042##
Commercially available t-butyl carbazate (14a) can be coupled to an
acid (14b) wherein A'' is as defined above, in a peptide coupling
reaction using standard procedure to give the corresponding Boc
protected hydrazide (14c). Removal of the Boc group using standard
conditions like acidic treatment, for example with TFA in
dichloromethane provides the unprotected hydrazide (8h).
Compounds according to formula I wherein E is CH and n is 0 or 1,
can be prepared as exemplified in scheme 15.
##STR00043##
The aldehyde (15b) can be prepared by subjecting a desired amino
acid or homo amino acid derivative (15a) to
N,O-dimethylhydroxylamine under peptide coupling conditions such as
in the presences of EDAC, HOBT, triethylamine or the like, followed
by reduction of the formed Weinreb amide with a reducing agent like
LiAlH.sub.4. Coupling of the formed aldehyde with a phosphonate
(15c) in a Horner-Emmons reaction as described for example by A.
Nadine et al. in Bioorg. Med. Chem. Lett., 2003, 13, 37-41,
provides alkene (15e). The double bond can then be epoxidized using
for instance mCPBA and the formed epoxide (15f) opened reductively
by hydrogenation in the presence of a catalyst like Pt(IV)O as
described in scheme 8. Subsequent coupling of the remaining
fragments, A'' and A' defined as for general formula I, using
standard peptide coupling methods, i.e. removal of the boc group,
coupling of the acid A''COOH followed by hydrolysis of the ester
group and coupling of the amine A'-NH.sub.2 yields the amide (15h).
Compounds wherein A'' is according to formula (VI) are conveniently
prepared by reacting the N-unprotected derivative of (15g) with an
activated carbonate or chloroformate of the desired derivative,
prepared as described in scheme 4, instead of with the acid
A''-COOH.
The hydroxy group of compound (15h) can be converted to a fluoride
or a primary or secondary amine thus providing compounds according
to general formula I wherein X is H, E is CH and L is F,
NHC.sub.1-C.sub.3alkyl or N(C.sub.1-C.sub.3alkyl).sub.2, as shown
in scheme 16 below.
##STR00044##
Reaction of alcohol (15h) with a suitable fluorinating agent such
as DAST or Deoxofluor or the like in a solvent like dichloromethane
as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis,
17, 1999, p. 2561-2578, yields the corresponding fluoro compound
(16a). Alternatively, the hydroxy group of compound 15h can be
transferred to an amine using any convenient method described in
the literature. For example the Mitsunobu procedure can be used,
i.e. reaction of the alcohol (15h) with an azodicarboxylate such as
DIAD or the like in the presence of triphenylphosphine followed by
displacement with a desired amine which provides the corresponding
amino derivative (16b). An alternative route to the amine (16b) is
by transformation of the hydroxy group into a leaving group such as
a derivative of sulphonic acid like a mesylate, triflate, tosylate
or the like by treatment with the appropriate sulphonylating agent
in a solvent like for instance pyridine or dichloromethane
optionally in the presence of triethylamine or the like, followed
by displacement of the leaving group with a desired primary or
secondary amine NH.sub.2C.sub.1-C.sub.3alkyl or
NH(C.sub.1-C.sub.3alkyl).sub.2. Alternatively, the leaving group
can be displaced with azide, or the hydroxy group can be converted
directly to an azide by use of an azide transfer agent like
diphenyl phosphoryl azide (DPPA), subsequent reduction of the
introduced azide to an amine, by for example triphenylphosphine
optionally in the presence of a base like triethylamine provides
compounds wherein L is NH.sub.2 whereas a reductive amination of
the afforded amine with a desired aldehyde or ketone provides
secondary or tertiary amines.
Dihydroxylated or difluorinated compounds wherein E is CH and
X=L=OH or F and n is 0 or 1 in general formula I can be prepared as
depicted in scheme 17.
##STR00045##
Hydrolysis of the epoxide (15f) obtained from scheme 15 can be
performed by using any convenient procedure known in the art, like
for example subjection of the epoxide to acidic conditions such as
treatment with a protic acid for example diluted perchloric acid,
sulphuric acid or formic acid or with a Lewis acid such as
BiCl.sub.3 in a solvent like tetrahydrofuran or the like, which
gives the diol (17a). Subsequent coupling of the acid A''-COOH and
the amine A'-NH.sub.2 as described in scheme 15 gives the dihydroxy
amid (17b). If desired, the two hydroxy groups can then be
converted to fluorides by using a fluorinating reagent such as
DAST, Deoxofluor or the like to give the difluorohydrazide
(17c).
A route to compounds according to general formula I wherein E is
CH, X is OH, L is F and n is 0 or 1 is illustrated in scheme
18.
##STR00046##
Opening of the epoxide (15f) by use of a fluorinating agent such as
(HF).sub.x/pyridine as described i.a. by Baklouti, A. et al. in
Synthesis 1999, p. 85-89 or (i-PrO).sub.2TiF.sub.2-ET.sub.4NF-nHF
as described by Hara, S. et al. in Tetrahedron 55, 1999, p.
4947-4954 or any other suitable fluorinating agent provides the
fluorohydrine (18a). Subsequent coupling, in any suitable order, of
the acid A''-COOH and the amine A'-NH.sub.2 as described in scheme
7 gives the fluorohydrine (18d). If desired, the hydroxy group of
any of compounds 18a, 18b or 18c can be converted to a fluoride by
treatment with DAST or the like, as previously described, thus
providing an alternative route to compounds according to general
formula I wherein X and L are F.
Compounds according to general formula I wherein E is CH, L is OH,
F, NHC.sub.1-C.sub.3alkyl or N(C.sub.1-C.sub.3alkyl).sub.2, X is
C.sub.1-C.sub.3alkyl and n is 0 or 1 can be prepared as illustrated
in scheme 19.
##STR00047##
Alkylation of the epoxide (15f) prepared ad described in scheme 15,
using an organocopper reagent such as a lithium dialkylcuprate in a
solvent like diethyl ether or THF or the like provides the
alkylated compound (19a). Coupling of the acid A''-COOH and the
amine A'-NH.sub.2, in any suitable order, as described in scheme 15
then gives the hydrazide derivative (19b). If desired, the hydroxy
group of compound 19b can be converted to a fluoride by treatment
with DAST or the like thus providing compounds according to general
formula I wherein L is F, or the hydroxy group can be converted to
an amine for example by way of a Mitsunobu reaction by treatment
with the desired amine in the presence of DIAD or the like or by
transformation of the hydroxy group to an azide followed by
reduction of the azide to an amine, thus providing compounds
according to general formula I wherein L is NH.sub.2 or the
afforded amine can be reacted in a reductive amination with a
desired aldehyde or ketone as previously described, thus providing
compounds according to general formula I wherein L a substituted
amine.
An alternative route to compounds wherein E is CH and n is 1 is
shown in scheme 20.
##STR00048##
Bromoderivative (20b) can be prepared from a suitable alkylated
malonate derivative (20a), by a hydrolysation-reduction procedure
followed by transformation of the formed primary alcohol to a
bromide as described by Jew et al. in Heterocycles, 46, 1997, p.
65-70. Alkylated malonate derivatives are available either
commercially or by alkylation of diethyl malonate with a desired
alkylating agent according to literature procedures well known by
the skilled person. The tertiary alcohol of the afforded
bromoderivative (20b) can optionally be protected for instance as
an acetate effected by treatment with acetic anhydride in pyridine
or the like and subsequently coupled to a copper-zinc reagent (20d)
prepared from a natural or non-natural amino acid, as described by
Dudu et al. in Tetrahedron 50, 1994, p. 2415-2432 to give (20e).
The remaining fragments, A'' and A' defined as for general formula
I, can then be introduced as described in scheme 15.
Substitution of the R.sup.2 group of any of the above described
compounds with a desired group using any suitable method known from
the literature can be performed at any convenient stage of the
synthesis. A method wherein a heteroaryl group is added to an aryl
group is exemplified in scheme 21.
##STR00049##
The aryl group of compound (21a) can be substituted with for
example an aryl or heteroaryl group such as a pyridyl group by
reacting the tri-n-butyltin derivative of the desired substituent
in a coupling reaction using a palladium(0) reagent such as
Pd(PPh.sub.3).sub.2Cl.sub.2 or the like in the presence of CuO in a
solvent like dimethylformamide at an elevated temperature effected
for instance by heating with microwaves.
It should be recognized that the strategy described in scheme 21 is
not restricted only to pyridyl groups but is also applicable to
other, optionally substituted, alkyl, aryl or heteroaryl groups. It
should also be recognized that other methods, many of which are
extensively described in the literature, may be used for the
substitution of the R.sup.2-group.
A general route to compounds according to formula I wherein n is 2
and E is N is shown in scheme 22.
##STR00050##
The two hydroxy groups of a desired 3-substituted
2-hydroxypropionic acid (22a) can be protected as a cyclic acetal
by reacting the acid with a suitable acetalisation reagent such as
2,2-dimethoxypropane or 2-methoxypropene under acidic conditions
achieved for example by the presence of a catalytic amount of
pyridinium tosylate (PPTS), pTS, CSA or the like, which gives the
cyclic acetal (22b). A subsequent Michael addition of methyl
acrylate to the afforded acetal in the presence of a base such as
LDA or the like then gives the .alpha.-alkylated compound (22c).
Hydrolysation of the acetal and ring closure of the afforded
intermediate alcohol, effected by treatment with an acid such as
TFA at an elevated temperature gives the lactone (22d). Coupling of
the amine A'-NH.sub.2 using standard peptide coupling conditions,
such as using reagents like EDAC, HOBt and optionally a base such
as triethylamine or the like and subsequent reductive opening of
the lactone using a reducing agent such as LiBH.sub.4 or the like
provides the diol (22f). The hydrazide derivative (22g) can then be
achieved by using any of the methods previously described. For
example the oxidation-reductive amination sequence described i.a.
in scheme 8 can be used, i.e. the primary hydroxy group is oxidised
to an aldehyde using any convenient oxidising agent like for
instance Dess-Martin periodinane, followed by a reductive amination
reaction with the desired hydrazide derivative in the presence of a
suitable reducing agent like Na(OAc).sub.3BH or the like.
Alternatively, the hydrazide moiety can be introduced by a
displacement reaction as described i.a. in scheme 10, i.e. the
primary alcohol is transferred to a leaving group such as a
mesylate or the like whereafter the leaving group is displaced by
the desired hydrazide derivative. If desired, the hydroxy
substituent of hydrazide (22g) can be converted to an amine or a
fluoro substituent using any of the previously described strategies
thus providing compounds according to general formula (I) wherein L
is F, NH.sub.2, NHC.sub.1-C.sub.6alkyl or
N(C.sub.1-C.sub.6alkyl).sub.2, X is H, n is 2 and E is N.
As will be appreciated by a person skilled in the field of organic
synthesis, the synthetic steps in the preparation of compounds
according to formula I can be performed in another order where
appropriate. For example, the substituent --CH.sub.2--R.sup.2 of
the hydrazide nitrogen of compounds wherein E is N, can be
introduced by using a substituted hydrazide derivative as
illustrated in scheme 1, or alternatively an unsubstituted or
optionally temporarily N-protected hydrazide derivative can be used
and the N-substituent introduced afterwards as illustrated in
scheme 8. It should also be realized that the introduction of the
amino and acid derivatives e.g. in scheme 18 and 19 can be
performed in the reversed order, i.e. the acid A''-COOH is coupled
prior to the amine A'-NH.sub.2.
Any functional groups present on any of the constituent compounds
used in the preparation of the compounds of the invention are
appropriately protected where necessary. For example
functionalities on the natural or non-natural amino acids are
typically protected as is appropriate in peptide synthesis. Those
skilled in the art will appreciate that the selection and use of
appropriate protecting groups depend upon the reaction conditions.
Suitable protecting groups are described in Greene, "Protective
Groups in Organic Synthesis", John Wiley & Sons, New York
(1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3,
Academic Press, New York (1981), the disclosure of which are hereby
incorporated by reference.
DETAILED DESCRIPTION
Various embodiments of the compounds of the invention and key
intermediates towards such compounds will now be described by way
of illustration only with reference to the accompanying
non-limiting chemistry and biology examples.
Chemistry. General Information. Analytical RP-LC-MS was performed
on a Gilson HPLC system with a Finnigan AQA quadropole mass
spectrometer using a Chromolith Performance RP-18e 4.6.times.100 mm
(Merck KGaA) column, with MeCN in 0.05% aqueous HCOOH as mobile
phase at a flow rate of 4 mL/min. Preparative RP-LC-MS was
performed on a Gilson HPLC system with a Finnigan AQA quadropole
mass spectrometer using a Zorbax SB-C8, 5 .mu.m 21.2.times.150 mm
(Agilent technologies) column, with MeCN in 0.05% aqueous HCOOH as
mobile phase at a flow rate of 15 mL/min. Optical rotations were
obtained on a Perkin-Elmer 241 polarimeter, specific rotations
([.alpha.]D) are reported in deg/dm and the concentration (c) is
given in g/100 mL in the specified solvent. .sup.1H and .sup.13C
NMR spectra were recorded on Varian Mercury Plus instruments at 300
and 75.45 MHz or 399.78 and 100.53 MHz respectively. Chemical
shifts are reported as 6 values (ppm) indirectly referenced to TMS
via the solvent residual signal. Flash column chromatography was
performed on Merck silica gel 60 (40-63 .mu.m) or Merck silica gel
60 RP-18 (40-63 .mu.m). Analytical thin layer chromatography was
done using aluminum sheets precoated with silica gel 60 F.sub.254.
UV light and an ethanolic solution of phosphomolybdic acid followed
by heating visualized components. Analytische Laboratorien,
Lindlar, Germany, performed elemental analyses.
Example 1
##STR00051##
2-Benzyl-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acryl amide (1)
2-Benzyl acrylic acid (J. Organomet., Chem. 646, 212-222, 2002)
(2.72 g, 16.8 mmol) was dissolved in EtOAc (50 mL) and EDAC (3.54
g, 18.5 mmol), HOBT (2.49 g, 18.4 mmol) and NMM (2.21 mL, 20.1
mmol) were added. The reaction mixture was stirred at room
temperature for 30 min and then (1S,2R)-1-amino-2-indanol (2.75 g,
18.4 mmol) was added and the stirring was continued over night.
Washing with saturated NaHCO.sub.3 (aq.) and brine followed by
drying (Na.sub.2SO.sub.4) and evaporation of the organic solvent
afforded the crude product, which were subjected to column
chromatography (silica, EtOAc/pentane, 40:60-50:50) yielding 2
(3.34 g, 68%) as a white solid.
[.alpha.].sub.D.sup.22+23.9.degree. (c 0.77, MeOH); .sup.1H NMR
(CDCl.sub.3) .delta. 7.40-7.11 (m, 8H), 6.97 (m, 1H), 6.42 (d,
J=8.27 Hz, 1H), 5.87 (s, 1H), 5.35 (m, 2H), 4.55 (m, 1H), 3.77 (d,
J=15.6 Hz, 1H), 3.70 (d, J=15.6 Hz, 1H), 3.14 (dd, J=5.21, 16.6 Hz,
1H), 2.89 (dd, J=1.89, 16.6 Hz, 1H), 2.18 (d, J=4.90 Hz, 1H);
.sup.13C NMR (CDCl.sub.3) .delta. 168.9, 144.3, 140.7, 140.1,
138.5, 129.2, 128.9, 128.4, 127.4, 126.9, 125.5, 124.6, 120.5,
73.7, 57.9, 40.0, 39.2. MS (m/z 294, M+H.sup.+, 587); Anal.
(C.sub.19H.sub.19NO.sub.2) C, H, N.
Example 2
##STR00052##
(2S)-2-Benzyl-oxirane-N-[(1S,2R)-2-hydroxy-indan-1-yl]-2-carboxylic
acid amide((S)-3) (2a) and
(2R)-2-Benzyl-oxirane-N-[(1S,2R)-2-hydroxy-indan-1-yl]-2-carboxylic
acid amide((R)-3) (2b)
Compound 1 (1.57 g, 5.36 mmol) was dissolved in CH.sub.2Cl.sub.2
(30 mL) and mCPBA (77%, 2.40 g, 10.7 mmol) was added. The reaction
mixture was heated to reflux for 48 h, cooled and washed with 10%
Na.sub.2S.sub.2O.sub.3 (aq.), saturated NaHCO.sub.3 (aq.) and
brine. The organic phase was dried (Na.sub.2SO.sub.4), filtered and
evaporated, and then the crude product was purified by column
chromatography (silica, EtOAc/pentane, 40:60-100:0) yielding the
two diastereomeric epoxides; 2a (0.414 g) as a pale yellow solid
and 2b (0.460 g) as a white solid in a total yield of 53%.
2a: R.sub.f=0.58 (EtOAc/pentane 50:50);
[.alpha.].sub.D.sup.19-60.1.degree. (c 1.00, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD) .delta. 7.35-7.11 (m, 8H), 7.07 (m, 1H), 5.18 (d,
J=5.12 Hz, 1H), 4.42 (ddd, J=1.50, 4.97, 5.12 Hz, 1H), 3.63 (d,
J=14.8 Hz, 1H), 3.11 (dd, J=4.97, 16.5, 1H), 2.97 (d, J=14.8 Hz,
1H), 2.91 (d, J=4.99 Hz, 1H), 2.87 (dd, J=1.50, 16.5, 1H), 2.85 (d,
J=4.99 Hz, 1H); .sup.13C NMR (CDCl.sub.3) .delta. 170.4, 140.4,
140.0, 136.0, 130.1, 128.7, 128.6, 127.38, 127.39, 125.6, 124.2,
73.4, 60.4, 57.5, 53.0, 39.6, 37.2; MS (m/z 310, M+H.sup.+, 619);
Anal. (C.sub.19H.sub.19NO.sub.3) C, H, N.
2b R.sub.f=0.13 (EtOAc/pentane 50:50);
[.alpha.].sub.D.sup.19+73.3.degree. (c 1.00, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3 1:1+2 drops of D.sub.2O) .delta.
7.37-7.08 (m, 7H), 6.98 (m, 1H), 6.41 (m, 1H), 5.16 (ddd, J=1.14,
5.04, 9.23 Hz, 1H), 4.43 (ddd, J=1.33, 4.97, 5.04 Hz, 1H), 3.73 (d,
J=14.5 Hz, 1H), 3.07 (m, 1H), 3.00 (d, J=5.09 Hz, 1H), 2.93 (d,
J=5.09 Hz, 1H), 2.84 (m, 1H), 2.75 (d, J=14.5 Hz, 1H); .sup.13C NMR
(CD.sub.3OD/CDCl.sub.3 1:1+2 drops of D.sub.2O) .delta. 171.3,
141.1, 140.6, 136.7, 130.5, 129.0, 128.5, 127.6, 127.5, 125.6,
124.7, 73.3, 60.8, 57.4, 53.4, 40.5, 37.8; MS (m/z 310, M+H.sup.+,
619); Anal. (C.sub.19H.sub.19NO.sub.3) C, H, N.
General Procedure for the Preparation of Hydrazides
Benzylhydrazine.times.2HCl and Et.sub.3N in EtOAc (20 mL) were
allowed to stir for 30 min at room temperature and then added to a
solution of N-functionalised amino acid (below), EDAC, HOBT and NMM
in EtOAc (40 mL) after which the reaction mixture was allowed to
stir overnight at room temperature. Dilution with EtOAc, washing
with saturated NaHCO.sub.3 (aq.), H.sub.2O and brine followed by
drying (Na.sub.2SO.sub.4), filtration and concentration of the
organic phase under vacuum afforded the crude product which was
purified by column chromatography (silica, CHCl.sub.3/MeOH,
100:0-95:5).
Example 3
##STR00053##
[(1S)-1-(N'-Benzyl-hydrazinocarbonyl)-2-methyl-propyl]-carbamic
acid benzyl ester (3)
The general procedure for the preparation of hydrazides described
above was followed using Cbz-(L)-valine (0.540 g, 2.15 mmol), EDAC
(0.450 g, 2.35 mmol), HOBT (0.320 g, 2.37 mmol), NMM (0.260 mL,
2.36 mmol), benzylhydrazine.times.2HCl (0.500 g, 2.56 mmol) and
Et.sub.3N (0.710 mL, 5.09 mmol) which gave the title compound
(0.502 g, 66%) as a white solid.
[.alpha.].sub.D.sup.21 -41.7.degree. (c 0.35, MeOH/CH.sub.2Cl.sub.2
50:50); .sup.1H NMR (DMSO-d.sub.6 +2 drops of D.sub.2O) .delta.
7.42-7.18 (m, 10H), 5.01 (s, 2H), 3.82 (s, 2H), 3.72 (d, J=7.61,
1H), 1.83 (m, 1H), 0.78 (d, J=6.86, 3H), 0.76 (d, J=6.86, 3H);
.sup.13C NMR (DMSO-d.sub.6+2 drops of D.sub.2O) .delta. 170.8,
156.7, 139.2, 137.7, 129.1, 129.0, 128.8, 128.5, 128.3, 127.6,
66.1, 59.5, 55.0, 30.9, 19.7, 19.0; MS (m/z 356, M+H.sup.+); Anal.
(C.sub.20H.sub.25N.sub.3O.sub.3) C, H, N.
Example 4
##STR00054##
[(1S)-1-(N'-Benzyl-hydrazinocarbonyl)-2,2-dimethyl-propyl]-carbamic
acid benzyl ester (4)
The general procedure for the preparation of hydrazides described
above was followed using Cbz-(L)-tert-leucine (2.00 g, 4.48 mmol),
EDAC (0.969 g, 5.05 mmol), HOBT (0.669 g, 4.95 mmol), NMM (0.542
mL, 4.93 mmol), benzylhydrazine.times.2HCl (0.962 g, 4.93 mmol) and
Et.sub.3N (1.38 mL, 9.85 mmol) which gave the title compound (1.11
g, 67%) as a low melting solid.
[.alpha.].sub.D.sup.19 -17.5.degree. (c 1.0, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD) .delta. 7.38-7.15 (m, 10H), 5.05 (d, J=12.3 Hz,
1H), 4.99 (d, J=12.3 Hz, 1H), 3.99 (s, 1H), 3.90 (s, 2H), 0.92 (s,
9H); .sup.13C NMR (CD.sub.3OD) .delta. 171.3, 158.0, 138.6, 137.9,
129.8, 129.3, 129.2, 128.9, 128.7, 128.3, 67.6, 62.5, 56.2, 35.2,
27.0; MS (m/z 370, M+H.sup.+); Anal.
(C.sub.21H.sub.27N.sub.3O.sub.3) C, H, N.
Example 5
##STR00055##
[(1S)-1-(N'-Benzyl-hydrazinocarbonyl)-2-methyl-propyl]-carbamic
acid methyl ester (5)
The general procedure for the preparation of hydrazides described
above was followed using N-(methoxycarbonyl)-(L)-valine (J. Med.
Chem., 39, 3203-3216, 1996) (2.11 g, 12.0 mmol), EDAC (2.41 g, 12.6
mmol), HOBT (1.70 g, 12.6 mmol), NMM (1.38 mL, 12.6 mmol),
benzylhydrazine.times.2HCl (2.45 g, 12.6 mmol) and Et.sub.3N (3.52
mL, 25.0 mmol), which gave the title compound (2.08 g, 65%) as a
light yellow solid.
[.alpha.].sub.D.sup.19 -45.5.degree. (c 1.0, CHCl.sub.3); .sup.1H
NMR (CDCl.sub.3) .delta. 8.00 (s, 1H) 7.40-7.25 (m, 5H), 5.50 (d,
J=9.04 Hz, 1H), 4.85 (s, 1H), 3.96 (s, 2H), 3.89 (dd, J=7.04, 9.04,
1H), 3.64 (s, 3H), 2.05 (m, 1H), 0.94 (d, J=4.94 Hz, 3H), 0.92 (d,
J=4.94 Hz, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 171.2, 157.3,
137.5, 129.2, 128.7, 127.9, 59.4, 56.1, 52.6, 31.2, 19.4, 18.2; MS
(m/z 280, M+H.sup.+, 559); Anal. (C.sub.14H.sub.21N.sub.3O.sub.3)
C, H, N.
Example 6
##STR00056##
[(1S)-1-(N'-Benzyl-hydrazinocarbonyl)-2,2-dimethyl-propyl]-carbamic
acid methyl ester (6)
The general procedure for the preparation of hydrazides described
above was followed using N-(methoxycarbonyl)-(L)-tert-leucine (J.
Med. Chem., 41, 3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g,
9.08 mmol), HOBT (1.22 g, 9.03 mmol), NMM (0.995 mL, 9.05 mmol),
benzylhydrazine.times.2HCl (1.61 g, 8.25 mmol) and Et.sub.3N (2.53
mL, 18.0 mmol) which gave the title compound (1.21 g, 50%) as a
light yellow solid.
[.alpha.].sub.D.sup.19 -40.7.degree. (c 0.98, CHCl.sub.3); .sup.1H
NMR (CDCl.sub.3) .delta. 8.07 (s, 1H) 7.38-7.24 (m, 5H), 5.63 (d,
J=9.64 Hz, 1H), 4.95 (s, 1H), 4.00 (d, J=12.4 Hz, 1H), 3.95 (d,
J=12.4 Hz, 1H), 3.92 (d, J=9.64 Hz, 1H), 3.68 (s, 3H), 0.98 (s,
9H); .sup.13C NMR (CDCl.sub.3) .delta.170.2, 157.1, 137.3, 128.9,
128.4, 127.6, 61.1, 55.8, 52.3, 34.5, 26.4; MS (m/z 294,
M+H.sup.+); Anal. (C.sub.15H.sub.23N.sub.3O.sub.3) C, H, N.
Example 7
##STR00057##
N-[(1S)-1-(N'-Benzyl-hydrazinocarbonyl)-2,2-dimethyl-propyl]-methane
sulfonamide (7)
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M
NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a
stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in
THF (7.6 mL) and H.sub.2O (12 mL) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 3 h and then at room
temperature overnight. The mixture was acidified with 4M HCl and
extracted with EtOAc. The organic phase was separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric
acid (0.486 g, 30%), which was analyzed by NMR and then used
without further purification. The general procedure for the
preparation of hydrazides described above was then followed using
the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid
(0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g,
2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine.times.2HCl
(0.489 g, 2.51 mmol) and Et.sub.3N (0.700 mL, 4.98 mmol) which gave
the title compound (0.416 g, 58%) as a white solid.
[.alpha.].sub.D.sup.21 +24.4.degree. (c 1.02, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD) .delta. 7.44-7.20 (m, 5H), 4.01 (d, J=13.1 Hz,
1H), 3.95 (d, J=13.1 Hz, 1H), 3.47 (s, 1H), 2.71 (s, 3H), 0.94 (s,
9H); .sup.13C NMR (CD.sub.3OD) .delta. 171.1, 139.0, 129.9, 129.5,
128.5, 64.5, 56.1, 40.8, 35.3, 27.0; MS (m/z 314, M+H.sup.+); Anal.
(C.sub.14H.sub.23N.sub.3O.sub.3S) C, H, N.
Example 8
##STR00058##
1-Benzyl-3-[(1S)-1-(N'-benzyl-hydrazinocarbonyl)-2,2-dimethyl-propyl]-urea
(8)
(L)-tert-Leucine (0.500 g, 3.81 mmol) was dissolved in dioxane (23
mL) and 2M NaOH (6.3 mL, 12.6 mmol) was added. After stirring for
10 min, phenylisocyanate (0.900 mL, 7.29 mmol) was added drop wise
to yield a clear solution. The reaction mixture was stirred at room
temperature for 18 h and then made acidic by addition of
concentrated HCl and thereafter extracted with EtOAc. The organic
phase was dried and evaporated to afford
(2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.36 g, 36%
yield), which was analysed by NMR and then used without further
purification. The general procedure for the preparation of
hydrazides described above was then followed using the crude
(2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyric acid (0.646 g, 2.44
mmol), EDAC (0.515 g, 2.67 mmol), HOBT (0.363 g, 2.69 mmol), NMM
(0.300 mL, 2.73 mmol), benzylhydrazine.times.2HCl (0.528 g, 2.71
mmol) and Et.sub.3N (0.753 mL, 5.38 mmol). The product was filtered
through a short silica column (CHCl.sub.3/MeOH, 100:0-95:5) and
then used without further purification in the next step.
Example 9
##STR00059##
{(1S)-1-[N'-(4-Bromo-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carba-
mic acid methyl ester (9)
N-(Methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401,
1998) (1.74 g, 9.20 mmol) was dissolved in EtOAc (50 mL) and EDAC
(1.94 g, 10.1 mmol), HOBT (1.37 g, 10.1 mmol), and NMM (1.11 mL,
10.1 mmol) were added. The reaction mixture was stirred at room
temperature for 30 min and then 4-bromo-benzylhydrazine (prepared
as described in Zh. Org. Khim., 28, 43-50, 1992) (2.31 g, 11.5
mmol) in EtOAc (20 mL) was added and the stirring was continued
over night. The reaction mixture was washed with saturated
NaHCO.sub.3 (aq.), H.sub.2O and brine and then the organic phase
was dried (Na.sub.2SO.sub.4), filtered and evaporated. The crude
product was purified by column chromatography (silica,
CHCl.sub.3/MeOH, 100:0-96:4) yielding the title compound (1.85 g,
54%) as a white solid.
[.alpha.].sub.D.sup.22 -26.4.degree. (c 0.84, MeOH); .sup.1H NMR
(CD.sub.3OD) .delta. 7.45 (m, 2H), 7.29 (m, 2H), 3.90 (s, 2H), 3.81
(s, 1H), 3.64 (s, 3H), 0.90 (s, 9H); .sup.13C NMR (CD.sub.3OD)
.delta. 170.5, 157.9, 137.2, 131.3, 130.8, 121.0, 61.7, 54.2, 51.5,
33.9, 25.8; MS (m/z 372, M+H.sup.+, 374, M+H.sup.+); Anal.
(C.sub.15H.sub.22BrN.sub.3O.sub.3) C, H, N.
Example 10
##STR00060##
{(1S)-1-[N'-(4-Bromo-benzyl)-hydrazinocarbonyl]-2-methyl-propyl}-carbamic
acid benzyl ester (10)
Cbz-(L)-Valine (1.04 g, 4.14 mmol) was dissolved in EtOAc (50 mL)
and EDAC (0.870 g, 4.54 mmol), HOBT (0.610 g, 4.51 mmol), and NMM
(0.500 mL, 4.55 mmol) were added. The reaction mixture was stirred
at room temperature for 30 min and then 4-bromo-benzylhydrazine
(1.00 g, 4.97 mmol) in EtOAc (5 mL) was added and the stirring was
continued for 2 h. After evaporation of the solvent, CHCl.sub.3 was
added and the solution was washed with saturated NaHCO.sub.3 (aq.)
and brine followed by drying (Na.sub.2SO.sub.4), filtration and
evaporation of the organic solvent. The crude product was purified
by column chromatography (silica, CHCl.sub.3/MeOH, 100:0-95:5)
yielding the title compound (1.42 g, 79%) as a white solid.
[.alpha.].sub.D.sup.21 +6.2.degree. (c 0.47, DMF); .sup.1H NMR
(DMSO-d.sub.6 +2 drops of D.sub.2O) .delta. 7.53-7.18 (m, 9H), 4.98
(s, 2H), 3.79 (s, 2H), 3.69 (d, J=7.65 Hz, 1H), 1.80 (m, 1H), 0.75
(d, J=6.92 Hz, 3H), 0.72 (d, J=6.92 Hz, 3H); .sup.13C NMR
(DMSO-d.sub.6 +2 drops of D.sub.2O) .delta. 170.8, 156.6, 138.8,
137.7, 131.6, 131.4, 129.0, 128.5, 128.3, 120.6, 66.1, 59.5, 54.2,
30.8, 19.7, 19.0; MS (m/z 434, M+H.sup.+, 436, M+H.sup.+); Anal.
(C.sub.20H.sub.24BrN.sub.3O.sub.3) C, H, N.
General Procedures for Synthesis of Inhibitors
Method A. Epoxide 2a or 2b and hydrazide were dissolved in iPrOH (6
mL) and the reaction mixture was stirred at 80.degree. C. for the
time indicated. Evaporation of the solvent afforded the crude
product, which was subjected to purification as stated below.
Method B. Epoxide 2a or 2b and hydrazide was dissolved in dry THF
(30 mL) and Ti(OiPr).sub.4 was added under N.sub.2-atmosphere.
Stirring in room temperature for 2.5 h and then at 40.degree. C.
for 30 min was followed by addition of saturated NaHCO.sub.3 (aq.)
and Et.sub.2O and the resulting mixture was stirred in room
temperature for 10 min. Filtration and separation of the two
phases, drying of the organic phase (Na.sub.2SO.sub.4) and
evaporation yielded the crude product which was purified by column
chromatography (RP-silica, MeCN/H.sub.2O, 50:50-90:10).
Example 11
##STR00061##
{(1S)-1-[N'-Benzyl-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2-methyl-propyl}-carbamic
acid benzyl ester (11)
The title compound was prepared according to Method A by heating
epoxide 2a (0.0950 g, 0.307 mmol) and hydrazide 3 (0.218 g, 0.614
mmol) for 90 h. Purification by column chromatography (silica,
EtOAc/pentane 30:70-100:0) gave the product (0.112 g, 55%) as a
white solid.
[.alpha.].sub.D.sup.19 -10.8.degree. (c 0.94, DMF); .sup.1H NMR
(CD.sub.3OD) .delta. 7.38-6.97 (m, 18H), 6.81 (m, 1H), 5.04 (s,
2H), 4.99 (d, J=4.92 Hz, 1H), 4.20 (d, J=14.0 Hz, 1H), 4.11 (m,
1H), 4.02 (d, J=14.0 Hz, 1H), 3.87 (d, J=14.0 Hz, 1H), 3.61 (d,
J=7.18 Hz, 1H), 3.08-2.76 (m, 5H), 1.61 (m, 1H), 0.60 (d, J=6.81,
3H), 0.46 (d, J=6.81, 3H); .sup.13C NMR (CD.sub.3OD) .delta. 177.5,
173.2, 158.4, 142.1, 141.4, 138.6, 138.2, 137.6, 131.6, 129.8,
129.5, 129.2, 129.0, 128.9, 128.8, 128.7, 128.4, 127.7, 127.6,
126.0, 125.6, 79.3, 73.9, 68.1, 67.7, 62.9, 60.8, 58.5, 44.5, 40.8,
31.7, 19.2, 18.4; MS (m/z 665, M+H.sup.+); Anal.
(C.sub.39H.sub.44N.sub.4O.sub.6.times.0.25H.sub.2O) C, H, N: calcd,
70.03, 6.71, 8.38; found, 69.98, 6.56, 8.15.
Example 12
##STR00062##
{(1S)-1-[N'-Benzyl-N'-((2R)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2-methyl-propyl}-carbamic
acid benzyl ester (12)
The title compound was prepared according to Method A by heating
epoxide 2b (0.104 g, 0.336 mmol) and hydrazide 3 (0.240 g, 0.676
mmol) for 120 h. Purification of 0.170 g of the crude product by
RP-LC-MS (30 min gradient of 20-80% CH.sub.3CN in 0.05% aqueous
formic acid) gave the product (44 mg, 39%) as a white solid.
[.alpha.].sub.D.sup.19 +10.8.degree. (c 0.58, DMF);
.sup.1H NMR (CD.sub.3OD) .delta. 7.42-7.07 (m, 17H), 6.97 (m, 1H),
6.25 (m, 1H), 5.04 (d, J=5.22, 1H), 5.01 (s, 2H), 4.37 (m, 1H),
4.05 (s, 2H), 3.68 (m, 2H), 3.10-2.72 (m, 5H), 1.78 (m, 1H), 0.70
(d, J=6.74 Hz, 3H), 0.67 (d, J=6.74 Hz, 3H);
.sup.13C NMR (DMSO-d.sub.6) .delta. 174.2, 171.1, 156.6, 142.7,
140.9, 138.5, 137.7, 137.4, 131.3, 129.2, 130.0, 128.6, 128.44,
128.39, 128.3, 127.7, 127.6, 126.8, 126.7, 125.3, 124.7, 78.4,
72.7, 72.6, 68.0, 66.1, 61.7, 59.5, 56.8, 43.3, 30.9, 19.5,
18.6;
MS (m/z 664, M+H.sup.+); Anal. (C.sub.39H.sub.44N.sub.4O.sub.6) C,
H, N.
Example 13
##STR00063##
{(1S)-1-[N'-Benzyl-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic
acid benzyl ester (13)
The title compound was prepared according to Method A, using
epoxide 2a (0.0996 g, 0.322 mmol) and hydrazide 4 (0.143 g, 0.387
mmol) by heating for 96 h. Purification by column chromatography
(silica, EtOAc/pentane, 40:60-100:0) followed by RP-LC-MS (30 min
gradient of 20-100% CH.sub.3CN in 0.05% aqueous HCOOH) gave the
product (0.0880 g, 40%) as a white solid.
[.alpha.].sub.D.sup.19 -61.6.degree. (c 1.01, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD) .delta. 7.38-7.02 (m, 17H), 6.95 (m, 1H), 6.75 (m,
1H), 5.03 (s, 2H), 4.97 (d, J=5.01 Hz, 1H), 4.22 (d, J=14.3 Hz,
1H), 4.09 (ddd, J=1.50, 4.96, 5.01 Hz, 1H), 4.03 (d, J=14.3 Hz,
1H), 3.87 (d, J=13.8 Hz, 1H), 3.64 (s, 1H), 3.04-2.73 (m, 5H), 0.57
(s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 177.5, 172.3, 158.3,
142.0, 141.4, 138.8, 138.2, 137.6, 131.6, 129.6, 129.5, 129.3,
129.0, 128.9, 128.8, 128.7, 128.4, 127.7, 127.5, 126.0, 125.6,
79.2, 73.9, 68.4, 67.7, 63.0, 62.8, 58.5, 44.4, 40.1, 34.9, 26.6;
MS (m/z 679, M+H.sup.+); Anal. (C.sub.40H.sub.46N.sub.4O.sub.6) C,
H, N.
Example 14
##STR00064##
{(1S)-1-[N'-Benzyl-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2-methyl-propyl}-carbamic
acid methyl ester (14)
The title compound was prepared according to Method A using epoxide
2a (0.100 g, 0.323 mmol) and hydrazide 5 (0.117 g, 0.419 mmol),
heating for 96 h. Purification by column chromatography (silica,
EtOAc/pentane, 40:60-100:0) followed by RP-LC-MS (30 min gradient
of 20-100% CH.sub.3CN in 0.05% aqueous HCOOH) gave the product
(0.0358 g, 19%) as a white solid.
[.alpha.].sub.D.sup.19 -50.9.degree. (c 0.99, CHCl.sub.3); .sup.1H
NMR (CDCl.sub.3) .delta. 7.59 (s, 1H), 7.44-7.00 (m, 14H), 6.36 (s,
1H), 5.17 (m, 2H), 4.30 (d, J=13.0 Hz, 1H), 4.14 (m, 1H), 4.06 (d,
J=7.38 Hz, 1H), 4.02 (d, J=7.38 Hz, 1H), 3.78-3.62 (m, 4H),
3.06-2.74 (m, 5H), 1.81 (m, 1H), 1.72 (s, 1H), 0.66-0.52 (m, 7H);
.sup.13C NMR (CDCl.sub.3) .delta. 174.8, 171.4, 157.2, 140.6,
140.2, 136.8, 136.6, 130.9, 128.8, 128.7, 128.3, 128.1, 128.0,
127.2, 127.0, 125.3, 124.1, 78.3, 73.4, 67.1, 62.5, 59.3, 58.0,
52.8, 43.9, 39.1, 30.8, 18.9, 17.7; MS (m/z 589, M+H.sup.+); Anal.
(C.sub.33H.sub.40N.sub.4O.sub.6) C, H, N.
Example 15
##STR00065##
{(1S)-1-[N'-Benzyl-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic
acid methyl ester (15)
The title compound was prepared according to Method A from epoxide
2a (0.101 g, 0.326 mmol) and hydrazide 6 (0.125 g, 0.426 mmol) by
heating for 96 h. Column chromatography (silica, EtOAc/pentane,
40:60-100:0) followed by RP-LC-MS (30 min gradient of 20-100%
CH.sub.3CN in 0.05% aqueous HCOOH) gave the product (0.0919 g, 46%)
as a white solid.
[.alpha.].sub.D.sup.21 -44.8.degree. (c 1.01, CHCl.sub.3); .sup.1H
NMR (CDCl.sub.3) .delta. 7.53 (s, 1H), 7.44-6.98 (m, 14H), 6.52 (s,
1H), 5.43 (d, J=9.04 Hz, 1H), 5.15 (dd, J=4.64, 9.04 Hz, 1H), 4.35
(d, J=14.7 Hz, 1H), 4.09 (m, 2H), 4.02 (d, J=14.7 Hz, 1H), 3.71 (m,
4H), 3.05-2.74 (m, 5H), 1.76 (s, 1H), 0.69 (s, 9H), 0.52 (m, 1H);
.sup.13C NMR (CDCl.sub.3) .delta. 174.8, 170.8, 157.3, 140.6,
140.2, 136.8, 136.7, 131.0, 128.8, 128.6, 128.2, 128.1, 128.0,
127.2, 127.0, 125.2, 124.3, 78.3, 73.4, 67.6, 62.2, 61.6, 57.8,
52.9, 43.9, 39.1, 34.6, 26.2; MS (m/z 603, M+H.sup.+); Anal.
(C.sub.34H.sub.42N.sub.4O.sub.6) C, H, N.
Example 16
##STR00066##
{(1S)-1-[N'-Benzyl-N'-((2R)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarba-
moyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic
acid methyl ester (16)
The title compound was prepared according to Method A from epoxide
2b (0.100 g, 0.323 mmol) and hydrazide 6 (0.147 g, 0.501 mmol) by
heating for 96 h. Purification by RP-LC-MS (30 min gradient of
20-100% CH.sub.3CN in 0.05% aqueous HCOOH) gave the product as a
white solid (0.103 g, 53%).
[.alpha.].sub.D.sup.21 -6.06.degree. (c 0.99, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD) .delta. 7.44-7.05 (m, 11H), 6.97 (m, 2H), 6.25 (d,
J=7.44 Hz, 1H), 5.08 (m, 1H), 4.40 (m, 1H), 4.09 (d, J=13.8 Hz,
1H), 4.02 (d, J=13.8 Hz, 1H), 3.70 (m, 2H), 3.56 (s, 3H), 3.10-2.77
(m, 5H), 0.76 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 176.5,
172.1, 158.8, 141.9, 141.2, 138.5, 137.6, 131.9, 130.0, 129.2,
129.0, 128.7, 128.4, 127.61, 127.56, 125.8, 125.4, 79.4, 74.1,
67.8, 63.1, 62.9, 58.2, 52.7, 44.1, 40.8, 35.1, 26.8; MS (m/z 603,
M+H.sup.+); Anal. (C.sub.34H.sub.42N.sub.4O.sub.6) C, H, N.
Example 17
##STR00067##
(2S)-2-Benzyl-3-[N-benzyl-N'-((2S)-2-methanesulfonylamino-3,3-dimethyl-but-
yryl)-hydrazino]-2-hydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-propionamide
(17)
The title compound was prepared according to Method A using epoxide
2a (0.100 g, 0.323 mmol) and hydrazide 7 (0.131 g, 0.418 mmol) by
heating for 96 h. Purification by column chromatography (silica,
EtOAc/pentane, 40:60-100:0) followed by RP-LC-MS (30 min gradient
of 20-100% CH.sub.3CN in 0.05% aqueous HCOOH) gave the product
(0.0864 g, 43%) as a white solid.
[.alpha.].sub.D.sup.21 -8.70.degree. (c 1.0, CHCl.sub.3); .sup.1H
NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 7.36-7.02 (m, 13H), 6.84
(m, 1H), 5.12 (d, J=5.04 Hz, 1H), 4.29 (ddd, J=5.11, 5.04, 1.94 Hz,
1H), 4.24 (d, J=14.5 Hz, 1H), 4.00 (d, J=14.5 Hz, 1H), 3.93 (d,
J=14.1 Hz, 1H), 3.15 (s, 1H), 3.07-3.96 (m, 2H), 2.90-2.83 (m, 2H),
2.74 (d, J=14.4 Hz, 1H), 2.42 (s, 3H), 0.51 (s, 9H); .sup.13C NMR
(CDCl.sub.3) .delta. 174.7, 170.2, 140.3, 139.9, 136.4, 136.2,
130.8, 128.5, 128.4, 128.3, 128.0, 127.9, 127.0, 126.8, 125.1,
124.1, 77.8, 73.1, 67.2, 63.6, 62.3, 57.4, 43.4, 40.9, 39.0, 34.2,
26.0; MS (m/z 623, M+H.sup.+). Anal.
(C.sub.33H.sub.42N.sub.4O.sub.6S) C, H, N.
Example 18
##STR00068##
(2S)-2-Benzyl-3-{N-Benzyl-N'-[(2S)-2-(3-benzyl-ureido)-3,3-dimethyl-butyry-
l]-hydrazino}-2-hydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-propionamide
(18)
The title compound was prepared according to Method A from epoxide
2a (0.0655 g, 0.212 mmol) and hydrazide 8 (0.102 g, 0.277 mmol) by
heating for 72 h. Purification by RP-LC-MS (30 min gradient of
0-90% CH.sub.3CN in 0.05% aqueous HCOOH) gave the product (0.0353
g, 25%) as a white solid.
[.alpha.].sub.D.sup.21 +30.7.degree. (c 0.45, CHCl.sub.3/MeOH,
2:1); .sup.1H NMR (CD.sub.3OD) .delta. 7.38-7.02 (m, 17H), 6.96 (m,
1H), 6.77 (m, 1H), 4.98 (d, J=4.98 Hz, 1H), 4.28 (s, 2H), 4.25 (d,
J=19.1 Hz, 1H), 4.05 (m, 2H), 3.90 (d, J=14.1 Hz, 1H), 3.76 (m,
1H), 3.05-2.76 (m, 5H), 0.58 (s, 9H); .sup.13C NMR (CD.sub.3OD)
.delta. 177.5, 173.0, 160.3, 142.0, 141.4, 141.1, 138.9, 137.6,
131.6, 129.6, 129.5, 129.3, 128.9, 128.7, 128.4, 128.2, 128.0,
127.6, 127.5, 126.0, 125.6, 79.3, 73.9, 68.5, 62.8, 61.3, 58.5,
44.7, 44.5, 40.8, 34.9, 26.7; MS (m/z 678, M+H.sup.+); Anal.
(C.sub.40H.sub.47N.sub.5O.sub.5) C, H, N.
Example 19
##STR00069##
{(1S)-1-[N'-(4-Bromo-benzyl)-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-
-1-ylcarbamoyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-c-
arbamic acid methyl ester (19)
The title compound was prepared according to Method B from epoxide
2a (0.250 g, 0.809 mmol) and hydrazide 9 (0.331 g, 0.889 mmol)
which gave the product (0.304 g, 55%) as a white solid.
[.alpha.].sub.D.sup.19 +2.65.degree. (c 0.72, DMF); .sup.1H NMR
(CD.sub.3OD) .delta. 7.35-7.03 (m, 11H), 6.92 (m, 1H), 6.77 (m,
1H), 4.96 (d, J=4.97 Hz, 1H), 4.14 (d, J=14.7 Hz, 1H), 4.13 (m,
1H), 4.02 (d, J=14.7 Hz, 1H), 3.87 (d, J=13.9 Hz, 1H), 3.60 (m,
4H), 3.09-2.75 (m, 5H), 0.60 (s, 9H); .sup.13C NMR (CD.sub.3OD)
.delta. 177.5, 172.4, 158.9, 142.1, 141.4, 138.2, 137.5, 132.3,
131.6, 131.4, 128.9, 128.8, 127.6, 127.4, 126.0, 125.6, 122.0,
79.2, 73.7, 68.4, 62.9, 62.0, 58.4, 52.7, 44.3, 40.7, 34.8, 26.6;
MS (m/z 681, M+H.sup.+, 683, M+H.sup.+); Anal.
(C.sub.34H.sub.41BrN.sub.4O.sub.6) C, H, N.
Example 20
##STR00070##
{(1S)-1-[N'-(4-Bromo-benzyl)-N'-((2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-
-1-ylcarbamoyl)-3-phenyl-propyl)-hydrazinocarbonyl]-2-methyl-propyl}-carba-
mic acid benzyl ester (20)
The title compound was prepared according to Method A from epoxide
2a (0.550 g, 0.178 mmol) and hydrazide 10 (0.0650 g, 0.150 mmol) by
heating for 168 h. Purification by RP-LC-MS (25 min gradient of
30-80% CH.sub.3CN in 0.05% aqueous HCOOH) gave the product (0.0172
g, 13%) as a white solid.
[.alpha.].sub.D.sup.22 -24.4.degree. (c 0.88, MeOH/DMF 2:1);
.sup.1H NMR (DMSO-d.sub.6 +2 drops of D.sub.2O) .delta. 7.40-7.01
(m, 16H), 6.76 (m, 2H), 4.97 (d, J=12.9 Hz, 1H), 4.93 (d, J=12.9
Hz, 1H), 4.87 (d, J=4.99 Hz, 1H), 4.05 (m, 3H), 3.72 (d, J=14.3 Hz,
1H), 3.51 (m, 1H), 3.02-2.55 (m, 5H), 1.53 (m, 1H), 0.53 (d, J=6.70
Hz, 3H), 0.39 (d, J=6.70 Hz, 3H); .sup.13C NMR (DMSO-d.sub.6 +2
drops of D.sub.2O) .delta. 175.2, 171.5, 156.6, 142.6, 141.1,
137.9, 137.6, 137.0, 131.3, 130.94, 130.86, 129.0, 128.5, 128.32,
128.27, 127.9, 126.9, 126.5, 125.5, 124.7, 120.6, 78.2, 72.3, 67.7,
66.1, 60.8, 59.5, 57.0, 43.4, 40.5, 30.5, 19.2, 18.6; MS (m/z 743,
M+H.sup.+, 745, M+H.sup.+); Anal.
(C.sub.39H.sub.43BrN.sub.4O.sub.6) C, H, N.
Example 21
Step a)
##STR00071##
3-[1-Phenyl-meth-(E)-ylidene]-dihydro-furan-2-one (21a)
The title compound was prepared as described in Tetrahedron, 57,
25, 2000, p. 5353-5360.
Step b)
##STR00072##
2-Phenyl-1,5-dioxa-spiro[2,4]heptan-4-one (21b)
To a solution of 3-[1-phenyl-meth-(E)-ylidene]-dihydro-furan-2-one
(21a) (4.0 g, 22.9 mmol) and 3-chloroperoxybenzoic acid (6.18 g,
27.6 mmol) in 1,2-dichloroetheane (70 mL) was added catalytic
amount of AIBN (50 mg) at 80.degree. C. and refluxed in the dark
for 6 h. The resulting solution was cooled and filtered, the
solvent was removed under reduced pressure, and the residue
dissolved in dichloromethane. The organic phase was washed
consecutively with saturated aqueous solutions of NaHCO.sub.3 (20
mL), KI (20 mL), Na.sub.2S.sub.2O.sub.3 (20 mL), and NaHCO.sub.3
(20 mL) then dried over anhydrous MgSO.sub.4 and evaporated under
reduced pressure. Product was purified by silica gel flash
chromatography using ethyl acetate:petroleum ether (1:4) gave 2.62
g in 60% yield of the title compound.
MS (ESI.sup.+): m/z: 191 (M.sup.++1) .sup.1H NMR (CDCl.sub.3, 400
MHz): .delta. 7.39 (m, 3H), 7.26 (m, 2H), 4.54 (dt, J=9.5 Hz, 3.3
Hz, 1H), 4.39 (s, 1H), 4.29 (m, 1H), 2.49 (m, 1H), 2.07 (m, 1H);
.sup.13C NMR (CDCl.sub.3, 100 MHz): .delta. 173.2, 133.1, 129.1,
128.8, 126.4, 64.8, 62.4, 61.7, 22.7
Step c)
##STR00073##
3-Benzyl-3-hydroxy-dihydro-furan-2-one (21c)
Method A: Platinum (IV) oxide (0.1 g) was added to a solution of
2-phenyl-1,5-dioxa-spiro[2.4]heptan-4-one (21b) (2.0 g, 10.5 mmol)
in ethyl acetate (40 mL) and placed in Parr hydrogenation set-up at
50 Psi for 3 h. Catalyst was filtered, and filtrate was evaporated
and purified by silica gel flash chromatography using petroleum
ether:ethyl acetate as eluent to give the title compound (1.3 g,
64% yield).
Method B: To a mixture of 2-phenyl-1,5-dioxa-spiro[2.4]heptan-4-one
(21b) (1.903 g, 10 mmol) and Pd/C (Degussa type E101 NE/W, 0.530 g,
2.5 mol % Pd) and 20 mL EtOAc in a reaction tube was added formic
acid (0.604 mL, 16 mmol) and triethylamine (2.09 mL, 15 mmol). The
tube was sealed with a screw cap and heated at 80.degree. C. for 3
h. The reaction mixture was allowed to cool to room temperature,
the catalyst was filtered off and volatiles were evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (Hex/EtOAc 1:1) which gave the title
compound as a colorless solid (1.851 g, 9.627 mmol, 96%).
MS (ESI.sup.+): m/z: 192 (M.sup.+) .sup.1H NMR (CDCl.sub.3, 400
MHz): .delta. 7.34-7.23 (m, 5H), 4.26 (m, 1H), 3.75 (m, 1H), 3.05
(s, 2H), 3.04 (s, 1H), 2.39-2.24 (m, 2H); .sup.13C NMR (CDCl.sub.3,
100 MHz): .delta. 178.9, 134.2, 130.1, 128.7, 128.5, 127.5, 75.5,
65.3, 43.4, 34.0
Step d)
##STR00074##
(S)-2-Benzyl-2,4-dihydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-butyramide
(21d-(S)) and
(R)-2-Benzyl-2,4-dihydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-butyramide
(21d-(S))
3-Benzyl-3-hydroxy-dihydro-furan-2-one (21c) (0.5 g, 2.6 mmol) and
2-hyroxypyridine (0.27 g, 2.8 mmol) in dry dichloromethane (15 mL)
was added (1S,2R)-(-)-cis-1-amino-2-indanol (0.43 g, 2.8 mmol). The
reaction mixture was stirred at 50.degree. C. for 24 h and then
evaporated. The residue was dissolved in ethyl acetate (80 mL) and
washed with 1M HCl (20 mL), followed by saturated aqueous
NaHCO.sub.3 (20 mL), and thereafter dried, filtered, and
concentrated. The residue purified by silica gel flash
chromatography using petroleum ether:acetone (3:1) gave 0.26 g of
first eluted (compound 21d-(S)) and 0.33 g of second eluted
(compound 21d-(R)) together in 66% yield of the title
compounds.
21d-(S): MS (ESI.sup.+): m/z: 342 (M.sup.++1)
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 7.64 (m, 1H),
7.31-7.10 (m, 9H), 5.52 (s, 1H), 5.05 (m, 2H), 4.73 (s, 1H), 4.16
(m, 1H), 3.61 (m, 2H), 3.05-3.00 (m, 2H), 2.86 (d, J=13.36 Hz, 1H),
2.76 (d, J=16.48 Hz, 1H), 2.14 (m, 1H), 1.73 (m, 1H); .sup.13C NMR
(DMSO-d.sub.6, 100 MHz): .delta. 174.8, 143.0, 141.0, 137.4, 130.9,
128.1, 127.7, 126.8, 126.6, 125.5, 124.5, 77.8, 72.4, 57.8, 56.9,
45.8, 41.4, 40.5 (hidden in DMSO)
21d-(R): MS (ESI.sup.+): m/z: 342 (M.sup.++1)
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.61 (d, J=8.79 Hz, 1H),
7.33-7.24 (m, 5H), 7.17-7.10 (m, 2H), 6.97 (m, 1H), 6.25 (d, J=7.32
Hz, 1H), 5.10 (m, 1H), 4.46 (m, 1H), 3.77 (m, 2H), 3.16 (d, J=13.36
Hz, 1H), 3.07 (dd, J=16.48, 4.94 Hz, 1H), 2.91 (d, J=13.36 Hz, 1H),
2.82 (d, J=16.48 Hz, 1H), 2.28 (m, 1H), 1.91 (m, 1H); .sup.13C NMR
(CD.sub.3OD, 100 MHz): .delta. 175.6, 140.4, 140.0, 136.5, 130.5,
127.6, 127.5, 126.2, 124.6, 123.8, 77.9, 72.7, 57.8, 56.9, 56.8,
45.5, 41.3, 39.3
Step e)
##STR00075##
(S)-2-Benzyl-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-N-((1S,2R)-2-hyd-
roxy-indan-1-yl)-butyramide (21e)
To a stirred solution of
(S)-2-benzyl-2,4-dihydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-butyramide(21-
d-(S)) (0.245 g, 0.72 mmol) and imidazole (0.73 g, 1.08 mmol) in
dry dichloromethane (25 mL) was added TBDPS-Cl (0.2 g, 0.75 mmol)
and left overnight. The reaction mixture was diluted, washed with
water, dried, evaporated and purified over silica gel flash
chromatography to yield 0.334 g (80%) of the title compound.
MS (ESI.sup.+): m/z: 580 (M.sup.+) .sup.1H NMR (CDCl.sub.3, 400
MHz): .delta. 7.71-7.66 (m, 4H), 7.48-7.36 (m, 8H), 7.34-7.24 (m,
4H), 7.22-7.18 (m, 2H), 7.12-7.04 (m, 2H), 5.37 (s, 1H), 5.24 (m,
1H), 4.17 (m, 1H), 4.15 (dd, J=10.4 Hz, 2.4 Hz, 1H), 4.10 (m, 1H),
3.10 (d, J=13.6 Hz, 1H), 3.05 (m, 2H), 2.81 (d, J=16.4 Hz, 1H),
2.40 (m, 1H), 2.15 (m, 1H), 1.09 (s, 9H); .sup.13C NMR (CDCl.sub.3,
100 MHz): .delta. 174.6, 140.5, 137.5, 135.7, 135.6, 132.4, 131.0,
130.4, 128.3, 128.2, 128.1, 127.1, 126.9, 125.3, 124.0, 80.9, 73.4,
63.5, 57.4, 46.0, 39.0, 38.8, 30.0, 27.0
Step f)
##STR00076##
(S)-2-Benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl--
8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-butan-1-one
(21f)
To a cooled (0.degree. C.) solution of
(S)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-N-((1S,2R)-2-hy-
droxy-indan-1-yl)-butyramide (21e) (0.325 g, 0.56 mmol) and
pyridinium p-toluenesulphonic acid (15 mg, 0.05 mmol) in dry
dichloromethane (20 mL), 2-methoxypropene (0.4 g, 5.6 mmol) was
added and stirred for 6 h at the same temperature. Saturated
NaHCO.sub.3 solution was added, organic layer and washed with sat.
NaHCO.sub.3, brine, dried over anhydrous MgSO.sub.4 and evaporated
under reduced pressure. The crude title product [(0.33 g), MS
(ESI.sup.+): 620 (M.sup.+)] was used as such for the next
reaction.
Step g)
##STR00077##
(S)-2-Benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazo-
l-3-yl)-2,4-dihydroxy-butan-1-one (21g)
TBAF (0.278 g, 1.06 mmol, 1M in THF) was added to a solution of
(S)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl-
-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-butan-1-one
(21f) (0.33 g, 0.53 mmol) in THF (20 mL) at room temperature and
stirred for 3 h. Solvent was evaporated and the residue dissolved
in dichloromethane and washed with water, brine, dried and
evaporated. The product purified by flash chromatography using
petroleum ether:acetone (4:1) to get 0.145 g of the title product
in 69% yield from two steps.
MS (ESI.sup.+): m/z: 382 (M.sup.++1) .sup.1H NMR (CDCl.sub.3, 400
MHz): .delta. 7.34-7.25 (m, 4H), 7.20-7.09 (m, 5H), 5.25 (m, 1H),
4.23 (m, 1H), 4.10-4.00 (m, 2H), 3.15 (d, J=12.8 Hz, 1H), 3.06 (dd,
J=16.4 Hz, 5.6 Hz, 1H), 2.96 (d, J=13.2 Hz, 1H), 2.83 (d, J=16.4
Hz, 1H), 2.40 (m, 1H), 2.16 (s, 6H), 2.10 (m, 1H); .sup.13C NMR
(CDCl.sub.3, 100 MHz): .delta. 175.4, 140.6, 140.4, 136.7, 130.9,
128.2, 128.0, 127.3, 127.2, 127.1, 125.4, 123.9, 80.2, 73.3, 61.2,
57.5, 46.2, 39.3, 39.2, 31.1, 29.4
Step h)
##STR00078##
(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazo-
l-3-yl)-3-hydroxy-4-oxo-butyraldehyde (21h)
A solution of (S)-2-benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3
aH-indeno[1,2-d]oxazol-3-yl)-2,4-dihydroxy-butan-1-one (21g) (0.13
g, 0.34 mmol) in dry CH.sub.2Cl.sub.2 (5 mL) was added over 1 min
to a stirred solution of Dess-Martin periodinate (0.16 g, 0.37
mmol) in dry CH.sub.2Cl.sub.2 (10 mL). After 30 min the homogeneous
mixture was diluted with ether and poured into cold saturated
NaHCO.sub.3 (10 mL) containing Na.sub.2S.sub.2O.sub.3 (2.2 g).
Organic layers were washed with aqueous saturated NaHCO.sub.3,
brine and dried (MgSO.sub.4). The solvents were evaporated below
20.degree. C. to give the title compound (0.082 g, 64%). The
residue [MS (ESI.sup.+): 380 (M.sup.++1)] was immediately used for
the next step.
Step i)
##STR00079##
((S)-1-{N'-[(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3
aH-indeno[1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyl]-hydrazinocarbonyl}-2,-
2-dimethyl-propyl)-carbamic acid methyl ester (21i)
(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3
aH-indeno[1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyraldehyde (21h)
(0.082 g, 0.21 mmol) and
[N-(methoxycarbony)-L-tert-leucinyl]hydrazine (0.048 g, 0.23 mmol,
prepared as reported JMC, 41, 3387, 1998) in dry THF (10 mL) was
stirred for 3 h and [the LCMS (ESI.sup.+) shows 565 (M.sup.+)],
then Na(OAc).sub.3BH (0.137 g, 0.64 mmol) was added and stirred
overnight. The reaction mixture was quenched with water and
evaporated. The residue was dissolved in dichloromethane and washed
with water, brine and dried. The crude product was analysed by LCMS
(ESI.sup.+) which showed 567 (M.sup.+) the title compound with a
minor quantity of the compound lacking the protection group on the
indanol moiety [MS (ESI.sup.+): 527 (M.sup.+)]. This mixture was
alkylated by the next step without purification.
Step j)
##STR00080##
((R)-(1-{N'-(4-Bromo-benzyl)-N'-[(R)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan--
1-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-car-
bamic acid methyl ester (22)
Compound 21i (0.105 g) was dissolved in 2-butanone (10 mL) and
added K.sub.2CO.sub.3 (0.045 g, 0.32 mmol), and 4-bromobenzyl
bromide (0.054 g, 0.21 mmol) and stirred at 80.degree. C. for 3 h.
Solvent was evaporated and the residue was dissolved in
dichloromethane (15 mL), washed with water, brine and cooled to
0.degree. C. TFA (1.0 mL) was added slowly and stirred for 30 min
then evaporated. Residue dissolved in dichloromethane (10 mL) and
washed with NaHCO.sub.3 solution, water, brine and dried. Residue
was purified by analytical preparative LCMS to yield 0.023 g (15%
overall yield) of the title compound.
MS (ESI.sup.+): m/z: 695, 697 (M.sup.+) .sup.1H NMR (CDCl.sub.3,
400 MHz): .delta. 7.40-7.12 (m, 1H), 7.04-6.98 (m, 2H), 6.42 (s,
1H), 6.08 (s, 1H), 5.18 (m, 2H), 4.16 (m, 1H), 3.97 (d, J=14.0 Hz,
1H), 3.77 (d, J=13.2 Hz, 1H), 3.66 (s, 3H), 3.56 (d, J=9.6 Hz, 1H),
3.12-3.01 (m, 4H), 2.82 (m, 2H), 2.32 (m, 1H), 1.94 (m, 1H), 0.79
(s, 9H)
Example 22
##STR00081##
((R)-(1-{N'-(4-Bromo-benzyl)-N'-[(S)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan--
1-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-car-
bamic acid methyl ester (22)
Compound 22d-(R) was taken through the steps a-j of example 21 as
described for compound 22-(S) which gave the title compound
Example 23
Step a)
##STR00082##
5,6-Dihydro-cyclopenta[b]thiophen-4-one (23a)
Over a period of 10 minutes a solution of triflic anhydride (84.7
g, 0.30 mol) in DCE (300 mL) was added to a cold solution of
N,N-dimethylacrylamide (29.8 g, 0.30 mol) in DCE (2700 mL). The
mixture was stirred for 15 minutes at 0.degree. C. A solution of
thiophene (25.3 g, 0.30 mol) was added and the mixture was refluxed
for seven hours. A solution of potassium carbonate (150 g in 200 mL
of water) was added. The mixture was extracted two times with DCM
dried over sodium sulphate and evaporated under reduced pressure.
The compound was purified by silica gel chromatography with ethyl
acetate/hexane.
Yield: 36.8 g=53%
.sup.1H-NMR CDCl.sub.3 7.32 (dd, 1H), 7.14 (dd, 1H), 3.20 (m, 2H),
3.00 (m, 2H)
Step b
##STR00083##
5-Hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one (23b)
5,6-dihydro-cyclopenta[b]thiophen-4-one (36.8 g, 0.266 mol) in MeOH
(1000 mL) was added at about 5.degree. C. to a solution of
potassium hydroxide 85% (52.7 g, 0.798 mol) in MeOH (500 mL).
Between 0.degree. C. and 5.degree. C. iodobenzene diacetate (94.4
g, 0.293 mol) was added in portions and the mixture was allowed to
come to room temperature. The mixture was stirred overnight at room
temperature. The mixture was evaporated and a 20% solution of
potassium carbonate (500 mL) was added. The mixture was extracted
for times with DCM dried with sodium sulphate and evaporated under
reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL)
and water (150 mL) and concentrated hydrochloric acid (150 mL) was
added. The mixture was stirred for two hours at room temperature.
The mixture was neutralized by the addition of potassium carbonate
and extracted four times with dichloromethane. The organic phase
was dried with sodium sulphate and evaporated under reduced
pressure. The product was crystallized with ether ethyl acetate and
the mother liquid was purified by silica gel chromatography with
toluene and acetone. Yield: 33.5 g=81.6%.
.sup.1H-NMR CDCl.sub.3 .delta. 7.36 (dd, 1H), 7.18 (d, 1H), 4.76
(m, 1H), 3.64 (m, 2H), 3.10 (m, 1H)
Step c)
##STR00084##
5-Hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one O-benzyl-oxime
(23c)
To a solution of 5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one
(33.4 g, 0.216 mol) in pyridine (300 mL) was added
O-benzylhydroxylamine hydrochloride (38.3 g, 0.240 mol) and the
mixture was stirred at room temperature over weekend. The mixture
was evaporated under reduced pressure and co-evaporated two times
with toluene. Ethyl acetate was added and the organic phase was
washed with 5% citric acid and brine. The organic phase was dried
with sodium sulphate and evaporated under reduced pressure. Yield.
55.1 g=98%
.sup.1H-NMR CDCl.sub.3 .delta. 7.40-7.20 (m, 7H), 5.20 (m, 3H),
3.45 (m, 2H), 3.0 (m, 1H)
Step d)
##STR00085##
cis-4-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-5-ol (racemate)
(23d)
A solution of 5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one
O-benzyl-oxime (55.1 g, 0.212 mol) was added drop wise at about
5.degree. C. to 1.0 M solution of borane in THF (650 mL) and the
mixture was stirred at room temperature overnight. The mixture was
refluxed for two hours and cooled to about 5.degree. C. Water (70
mL) and 20% potassium hydroxide solution (80 mL) was added
dropwise. The mixture was refluxed for two hours and cooled. Brine
was added and the THF removed under reduced pressure. The mixture
was extracted five times with DCM, dried with sodium sulphate and
evaporated under reduced pressure. The product was purified by
silica gel chromatography with DCM and 10% methanol. Yield: 17.8
g=54%
.sup.1H-NMR DMSO-d.sub.6 .delta. 7.30 (d, 1H), 6.92 (d, 1H), 4.46
(m, 1H), 4.20 (m, 1H) 3.99-3.84 (dd, 2H)
Example 24
Separation of the Enantiomeres from Example 23
Step a)
##STR00086##
[1-(5-Hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ylcarbamoyl)-2-phenyl-
-ethyl]-carbamic acid tert-butyl ester (24a)
To a mixture of the racemic
cis-4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-5-ol (17.5 g,
0.112 mol) in dry DMF (400 mL) was added Boc-L-phenylalanin (30.51
g, 0.115 mol) HOBT (15.6 g, 0.115 mol) and EDAC (22.0 g, 0.115
mol). To the stirred mixture was added TEA (16 mL, 0.115 mol) and
the mixture was stirred at room temperature overnight. The mixture
was added to 5% citric acid and extracted three times with ethyl
acetate. The organic phase was washed with brine and saturated
sodium hydrogen carbonate (two times). The organic phase was dried
with sodium sulphate and evaporated under reduced pressure. Yield:
43 g=95%
Step b)
##STR00087##
2-Amino-N-(5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-3-phenyl-p-
ropionamide (24b)
Compound 24a was dissolved in chloroform (400 mL) and TFA (100 mL)
was added and the mixture was stirred for three hours at room
temperature. The organic phase was washed two times with 15%
ammonia solution (300 mL) and with brine. The organic phase was
dried over sodium sulphate and evaporated. The product was purified
by silica gel chromatography with DCM with three to ten percent
methanol.
Yield A 12.5 g first diastereomere=40%
Yield B 12.5 g second diastereomere=40%
Step c)
##STR00088##
4-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-5-ol (24c)
The first diastereomere (12.4 g, 41 mmol) was dissolved in EtOH
(400 mL) and a solution of sodium hydroxide (21.0 g, 525 mmol)
water (300 mL) was added. The mixture was refluxed overnight. The
ethanol was removed and the alkaline phase was extracted six times
with DCM. The organic phase was washed with brine, dried with
sodium sulphate and evaporated under reduced pressure. Yield: 6.2
g=97%.
.sup.1H-NMR DMSO-d.sub.6 .delta. 7.30 (d, 1H), 6.92 (d, 1H), 4.46
(m, 1H), 4.20 (m, 1H), 3.99-3.84 (dd, 2H).
Example 25
##STR00089##
{(1S)-1-[N'-(3-Bromo-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carba-
mic acid methyl ester (25)
N-(Methoxycarbonyl)-(L)-tert-leucine (3.25 g, 17.1 mmol) was
dissolved in EtOAc (40 mL) and HOBT (2.55 g, 18.9 mmol), EDAC (3.62
g, 18.9 mmol) and NMM (2.08 mL, 18.9 mmol) were added subsequently.
3-Bromo-benzylhydrazine (4.14 g, 20.6 mmol), dissolved in EtOAc (20
mL) was added to the reaction mixture, which thereafter was stirred
at room temperature over night. The organic phase was washed with
saturated NaHCO.sub.3 (aq., 50 mL), H.sub.2O (50 mL) and brine (50
mL). The combined aqueous phases were extracted with EtOAc
(3.times.50 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude product was purified by column chromatography
(silica, CHCl.sub.3/MeOH, 100:0-95:5) to afford 2 (4.88 g, 76%).
RP-LC-MS (35 min gradient of 35-80% CH.sub.3CN in 0.05% aqueous
formic acid) was performed on a small fraction of the residue to
obtain a sample of higher purity for characterization and the
product was isolated as a white solid.
[.alpha.].sub.D.sup.20 -28.0.degree. (c 1.2, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 7.56 (m, 1H), 7.40 (m, 1H), 7.32
(m, 1H), 7.22 (m, 1H), 3.93 (s, 2H), 3.81 (s, 1H), 3.63 (s, 3H),
0.89 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 171.7, 159.0,
141.8, 132.9, 131.5, 131.1, 128.8, 123.3, 62.9, 55.5, 52.7, 35.1,
26.9;
MS (m/z 372, M+H.sup.+, 374, M+H.sup.+).
Example 26
##STR00090##
{(1S)-1-[N'-(3-Bromo-benzyl)-N'-[(2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-indan-
-1-ylcarbamoyl)-3-phenyl-propyl]-hydrazinocarbonyl]-2,2-dimethyl-propyl}-c-
arbamic acid methyl ester (26)
(2S)-2-Benzyl-oxirane-N-[(1S,2R)-2-hydroxy-indan-1-yl]-2-carboxylic
acid amide (0.930 g, 3.01 mmol) and compound 25 (1.23 g, 3.31 mmol)
were dissolved in dry THF (40 mL), Ti(OiPr).sub.4 (1.79 mL, 6.02
mmol) was added and the mixture was stirred at 40.degree. C. for 2
h. Et.sub.2O (100 mL) and saturated NaHCO.sub.3 (aq., 100 mL) was
added to the reaction mixture and the phases were separated. The
organic phase was then washed with H.sub.2O (2.times.200 mL). All
water phases were reextracted with CHCl.sub.3 (100 mL), and the
combined organic phases were dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (RP-silica, CH.sub.3CN/H.sub.2O,
50:50-70:30) affording 3 (0.95 g, 46%) as a light yellow solid.
[.alpha.].sub.D.sup.9 -55.2.degree. (c 0.95, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 7.50 (m, 1H), 7.36-7.16 (m, 7H),
7.13-6.93 (m, 4H), 6.80 (m, 1H), 4.96 (d, J=4.82 Hz, 1H), 4.17 (d,
J=14.7 Hz, 1H), 4.14 (m, 1H), 4.00 (d, J=14.7 Hz, 1H), 3.88 (d,
J=13.9 Hz, 1H), 3.60 (m, 4H), 3.07-2.77 (m, 5H), 0.60 (s, 9H);
.sup.13C NMR (CD.sub.3OD) .delta. 177.5, 172.4, 159.0, 142.0,
141.6, 141.4, 137.5, 132.2, 131.6, 131.5, 131.0, 128.9, 128.8,
128.2, 127.71, 127.67, 126.0, 125.5, 123.5, 79.2, 73.8, 68.6, 62.9,
62.0, 58.4, 52.7, 44.3, 40.7, 34.9, 26.6;
MS (m/z 681, M+H.sup.+, 683, M+H.sup.+).
General Procedures for the Pd-Catalyzed Reactions:
Method A. Aryl bromide 19 or 26, tin reagent,
Pd(PPh).sub.3Cl.sub.2, CuO and DMF (2 mL) were stirred in a
heavy-walled Smith process vial at 130.degree. C. for 20 min in the
microwave cavity. CH.sub.2Cl.sub.2 (30 mL) was added to the mixture
followed by washing with saturated NaHCO.sub.3 (aq., 3.times.20
mL). The organic phase was dried (Na.sub.2SO.sub.4), filtered and
evaporated. The residue was redissolved in CH.sub.3CN (70 mL) and
washed with isohexane (3.times.20 mL) after which the CH.sub.3CN
phase was evaporated and the crude product was purified using
RP-LC-MS.
Method B. Aryl bromide 19 or 26, boronic acid,
Pd(PPh).sub.3Cl.sub.2, 2 M Na.sub.2CO.sub.3 (aq.), EtOH and DME
were stirred in a heavy-walled Smith process vial at 120.degree. C.
for 30 min in the microwave cavity. Five drops of formic acid were
added to the mixture and then the solvent was evaporated. The
residue was redissolved in CH.sub.3CN/H.sub.2O/DMF and filtered
before purification by RP-LC-MS.
Method C. Aryl bromide 26, acetylene, Et.sub.2NH,
Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and DMF were stirred in a
heavy-walled Smith process vial at 140.degree. C. for 30-40 min.
Work up was performed by extracting the mixture with
CH.sub.2Cl.sub.2 (2 mL) and H.sub.2O (2.times.2 mL). The organic
phase was filtered and evaporated before the product was purified
by RP-LC-MS.
Method D. Aryl bromide 19, acetylene, Et.sub.3N,
Pd(PPh.sub.3).sub.2Cl.sub.2, CuI and DMF were stirred in a
heavy-walled Smith process vial at 130.degree. C. for 60 min.
Filtration and evaporation of most of the solvent yielded the crude
product which was purified by RP-LC-MS.
##STR00091##
{(1S)-1-[N'-(Biphenyl-4-yl-methyl)-N'-[(2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-
-indan-1-ylcarbamoyl)-3-phenyl-propyl]-hydrazinocarbonyl]-2,2-dimethyl-pro-
pyl}-carbamic acid methyl ester (27)
The title compound was prepared according to Method B, using
compound 19 (90.0 mg, 0.132 mmol), phenylboronic acid (80.5 mg,
0.660 mmol), Pd(PPh).sub.3Cl.sub.2 (4.60 mg, 0.0065 mmol), 2 M
Na.sub.2CO.sub.3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.6 mL) and DME
(2.4 mL). Purification by RP-LC-MS (40 min gradient of 10-100%
CH.sub.3CN in 0.05% aqueous formic acid) afforded the product (33.7
mg, 38%) as a white solid.
[.alpha.].sub.D.sup.20 -59.3.degree. (c 1.4, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 7.55-7.16 (m,
14H), 7.13-6.92 (m, 3H), 6.82 (m, 1H), 5.05 (d, J=4.80 Hz, 1H),
4.24 (d, J=14.3 Hz, 1H), 4.09 (m, 1H), 4.05 (d, J=14.3 Hz, 1H),
3.92 (d, J=14.0 Hz, 1H), 3.58 (m, 4H), 3.04-2.71 (m, 5H), 0.56 (s,
9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 176.2,
171.3, 157.9, 141.5, 141.0, 140.6, 140.5, 136.81, 136.78, 131.0,
129.3, 129.2, 128.4, 128.3, 127.6, 127.4, 127.3, 127.2, 127.1,
125.4, 124.8, 78.5, 73.3, 67.6, 61.9, 61.7, 57.8, 52.6, 43.8, 39.6,
34.6, 26.2;
MS (m/z 679, M+H.sup.+).
Example 28
##STR00092##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[4-(pyridin-2-yl)-benzyl]-hydrazinocarbonyl]-2,2-dimethyl--
propyl}-carbamic acid methyl ester (28)
The title compound was prepared according to Method A, using
compound 19 (100 mg, 0.147 mmol), 2-(1,1,1-tributylstannyl)pyridine
(220 mg, 0.598 mmol), Pd(PPh).sub.3Cl.sub.2 (5.12 mg, 0.0072 mmol)
and CuO (11.7 mg, 0.147 mmol). Purification by RP-LC-MS (40 min
gradient of 10-100% CH.sub.3CN in 0.05% aqueous formic acid) gave
the product (17.2 mg, 17%) as a white solid.
[.alpha.].sub.D.sup.19 -28.8.degree. (c 0.99, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 8.57 (m, 1H), 7.94-6.93 (m, 15H),
6.75 (m, 1H), 4.99 (m, 1H), 4.27 (d, J=14.3 Hz, 1H), 4.14 (m, 1H),
4.12 (d, J=14.3 Hz, 1H), 3.90 (d, J=14.9, 1H), 3.68-3.52 (m, 4H),
3.08-2.74 (m, 5H), 0.59 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta.
176.4, 171, 2, 157.8, 157.5, 149.1, 140.9, 140.2, 138.9, 138.3,
137.7, 136.4, 130.5, 128.9, 127.7, 127.6, 126.8, 126.5, 126.4,
124.8, 124.5, 122.5, 121.2, 78.1, 72.7, 67.2, 61.8, 61.3, 57.3,
51.5, 43.2, 39.6, 33.7, 25.4; HRMS (M+H.sup.+): 680.3450,
C.sub.39H.sub.46N.sub.5O.sub.6 required 680.3448.
Example 29
##STR00093##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N-[4-(pyridin-3-yl)-benzyl]-hydrazinocarbonyl]-2,2-dimethyl-p-
ropyl}-carbamic acid methyl ester (29)
The title compound was prepared according to Method A, using
compound 19 (90.0 mg, 0.132 mmol),
3-(1,1,1-tributylstannyl)pyridine (194 mg, 0.527 mmol),
Pd(PPh).sub.3Cl.sub.2 (4.63 mg, 0.0065 mmol) and CuO (10.5 mg,
0.132 mmol). The product (24.0 mg, 27%) was afforded as a white
solid after purification by RP-LC-MS (40 min gradient of 10-100%
CH.sub.3CN in 0.05% aqueous formic acid).
[.alpha.].sub.D.sup.19 -37.5.degree. (c 1.4, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 8.70 (m, 1H), 8.49 (m 1H), 7.99
(m, 1H), 7.56-7.42 (m, 5H), 7.34-7.18 (m, 5H), 7.15-6.94 (m, 3H),
6.72 (m, 1H), 4.99 (m, 1H), 4.27 (d, J=14.5 Hz, 1H), 4.13 (m, 1H),
4.11 (d, J=14.5 Hz, 1H), 3.91 (m, 1H), 3.66-3.53 (m, 4H), 3.07-2.76
(m, 5H), 0.59 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 176.4,
171, 2, 157.8, 147.5, 147.0, 140.9, 140.3, 138.2, 137.3, 136.5,
136.4, 135.2, 130.5, 129.3, 127.7, 127.6, 126.8, 126.5, 126.2,
124.8, 124.5, 124.3, 78.1, 72.6, 67.2, 61.7, 61.2, 57.3, 51.5,
43.2, 39.6, 33.7, 25.4;
HRMS (M+H.sup.+): 680.3465, C.sub.39H.sub.46N.sub.5O.sub.6 required
680.3448.
Example 30
##STR00094##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[4-(pyridin-4-yl)-benzyl]-hydrazinocarbonyl]-2,2-dimethyl--
propyl}-carbamic acid methyl ester (30)
The title compound was prepared according to Method B, using
compound 19 (90.0 mg, 0.132 mmol), pyridine-4-boronic acid (81.0
mg, 0.659 mmol), Pd(PPh).sub.3Cl.sub.2 (4.60 mg, 0.0065 mmol), 2 M
Na.sub.2CO.sub.3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.4 mL) and DME
(1.6 mL). Purification by RP-LC-MS (40 min gradient of 0-80%
CH.sub.3CN in 0.05% aqueous formic acid) yielded the product (15.6
mg, 17%) as a white solid.
[.alpha.].sub.D.sup.20-41.5.degree. (c 0.47, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 8.55 (m, 2H), 7.68-6.91 (m, 14H),
6.70 (m, 1H), 4.97 (d, J=5.15, 1H), 4.26 (d, J=14.6 Hz, 1H), 4.14
(m, 1H), 4.12 (d, J=14.6 Hz, 1H), 3.90 (m, 1H), 3.64-3.51 (m, 4H),
3.07-2.75 (m, 5H), 0.58 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta.
176.4, 171, 2, 157.8, 149.4, 149.3, 140.9, 140.3, 139.4, 136.7,
136.4, 130.4, 129.3, 127.7, 127.6, 126.8, 126.5, 126.2, 124.8,
124.5, 121.8, 78.1, 72.6, 67.3, 61.7, 61.2, 57.3, 51.5, 43.2, 39.6,
33.7, 25.4; HRMS (M+H.sup.+): 680.3432,
C.sub.39H.sub.46N.sub.5O.sub.6 required 680.3448.
Example 31
##STR00095##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[4-(pyrazin-2-yl)-benzyl]-hydrazinocarbonyl]-2,2-dimethyl--
propyl}-carbamic acid methyl ester (31)
The title compound was prepared according to Method A, using
compound 19 (91.3 mg, 0.134 mmol),
2-(1,1,1-tributylstannyl)pyrazine (198 mg, 0.537 mmol),
Pd(PPh).sub.3Cl.sub.2 (4.70 mg, 0.0067 mmol) and CuO (10.7 mg,
0.134 mmol). Purification by RP-LC-MS (35 min gradient of 20-90%
CH.sub.3CN in 0.05% aqueous formic acid) yielded the product (17.3
mg, 19%) as a white solid.
[.alpha.].sub.D.sup.20-26.5 (c 0.87, MeOH);
.sup.1H NMR (CD.sub.3OD) .delta. 9.00 (m, 1H), 8.65 (m, 1H), 8.49
(m, 1H), 7.88 (m, 2H), 7.47 (m, 2H), 7.34-6.91 (m, 8H), 6.72 (m,
1H), 4.97 (d, J=5.00, 1H), 4.27 (d, J=14.5 Hz, 1H), 4.14 (d, J=14.5
Hz, 1H), 4.13 (m, 1H), 3.90 (d, 1H), 3.63 (s, 1H), 3.57 (s, 3H),
3.05-2.77 (m, 5H), 0.59 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta.
177.5, 172.4 159.0, 154.1, 145.7, 143.9, 142.9, 142.1, 141.4,
141.2, 137.6, 136.6, 131.6, 130.3, 128.9, 128.8, 127.9, 127.7,
127.5, 126.0, 125.7, 79.3, 73.8, 68.4, 62.9, 62.5, 58.5, 52.7,
44.4, 40.8, 34.9, 26.6; HRMS (M+H.sup.+): 681.3385,
C.sub.38H.sub.44N.sub.6O.sub.6 requires 681.3401.
Example 32
##STR00096##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[4-(benzo[b]thiophen-2-yl)-benzyl]-hydrazinocarbonyl]-2,2--
dimethyl-propyl}-carbamic acid methyl ester (32)
The title compound was prepared according to Method B, using 19
(83.4 mg, 0.123 mmol), benzo[b]thiophene-2-boronic acid (109 mg,
0.613 mmol), Pd(PPh).sub.3Cl.sub.2 (4.32 mg, 0.00615 mmol), 2 M
Na.sub.2CO.sub.3 (aq., 0.185 mL, 0.369 mmol), EtOH (0.4 mL) and DME
(1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-100%
CH.sub.3CN in 0.05% aqueous formic acid) afforded the product (56.4
mg, 62%) as a white solid.
[.alpha.].sub.D.sup.19-68.5.degree. (c 1.0, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3 2:1) .delta. 7.82-7.67 (m, 3H),
7.58-7.06 (m, 11H), 7.10 (m, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.80
(m, 1H), 4.96 (d, J=5.04 Hz, 1H), 4.17 (d, J=14.5 Hz, 1H), 4.06 (m,
1H), 4.01 (d, J=14.5 Hz, 1H), 3.85 (d, J=13.9 Hz, 1H), 3.55 (s,
1H), 3.53 (s, 3H), 3.05-2.72 (m, 5H), 0.53 (s, 9H); .sup.13C NMR
(DMSO-d.sub.6, 60.degree. C. due to presence of rotamers at room
temperature) .delta. 174.4, 169.8, 156.1, 143.2, 141.8, 140.3,
140.1, 138.3, 138.2, 136.3, 132.0, 130.0, 128.6, 127.3, 126.8,
125.8, 125.6, 125.3, 124.4, 124.2, 123.9, 123.3, 122.1, 119.3,
119.2, 77.3, 71.6, 66.7, 61.1, 60.4, 56.4, 56.3, 51.1, 42.7, 33.2,
25.9; MS (m/z 735, M+H.sup.+).
Example 33
##STR00097##
{(1S)-1-[N'-(4-Benzo[1,3]dioxol-5-yl-benzyl)-N'-[(2S)-2-hydroxy-2-((1S,2R)-
-2-hydroxy-indan-1-ylcarbamoyl)-3-phenyl-propyl]-hydrazinocarbonyl]-2,2-di-
methyl-propyl}-carbamic acid methyl ester (33)
The title compound was prepared according to Method B, using
compound 19 (91.9 mg, 0.135 mmol), 3,4-methylenedioxyphenylboronic
acid (112 mg, 0.676 mmol), Pd(PPh).sub.3Cl.sub.2 (4.70 mg, 0.0067
mmol), 2 M Na.sub.2CO.sub.3 (aq., 0.203 mL, 0.405 mmol), EtOH (0.4
mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of
30-100% CH.sub.3CN in 0.05% aqueous formic acid) afforded the
product (47.7 mg, 49%) as a white solid.
[.alpha.].sub.D.sup.19-62.3.degree. (c 0.65, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3 2:1) .delta. 7.36-7.15 (m, 9H),
7.12-6.90 (m, 5H), 6.85-6.73 (m, 2H), 5.93 (s, 2H), 5.01 (d, J=4.88
Hz, 1H), 4.22 (d, J=14.2 Hz, 1H), 4.10 (m, 1H), 4.04 (d, J=14.2 Hz,
1H), 3.90 (d, J=13.8 Hz, 1H), 3.58 (m, 4H), 3.07-2.72 (m, 5H), 0.56
(s, 9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3 3:2) .delta. 176.7,
176.6, 171.6, 158.2, 148.9, 147.9, 141.02, 141.00, 140.9, 140.7,
136.9, 136.7, 136.1, 131.2, 129.5, 128.50, 128.46, 127.29, 127.25,
125.6, 125.1, 109.1, 107.9, 101.9, 78.7, 73.5, 67.8, 62.0, 58.05,
57.96, 52.7, 43.9, 40.0, 34.7, 26.3; MS (m/z 723, M+H.sup.+).
Example 34
##STR00098##
{(1S)-1-[N'-[4-(3,5-Dimethyl-isoxazol-4-yl)-benzyl]-N'-[(2S)-2-hydroxy-2-(-
(1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-phenyl-propyl]-hydrazinocarbonyl]-
-2,2-dimethyl-propyl}-carbamic acid methyl ester (34)
The title compound was prepared according to Method B, using
compound 19 (95.1 mg, 0.139 mmol), 3,5-dimethylisoxazole-4-boronic
acid (98.5 mg, 0.699 mmol), Pd(PPh).sub.3Cl.sub.2 (4.84 mg, 0.0069
mmol), 2 M Na.sub.2CO.sub.3 (aq., 0.210 mL, 0.419 mmol), EtOH (0.4
mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of
20-90% CH.sub.3CN in 0.05% aqueous formic acid) afforded the
product (30.2 mg, 31%) as a white solid.
[.alpha.].sub.D.sup.20-53.5.degree. (c 0.72, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD) .delta. 7.42 (m, 2H), 7.34-7.16 (m, 5H),
7.15-6.96 (m, 5H), 6.71 (m, 1H), 4.97 (d, J=5.11 Hz, 1H), 4.27 (d,
J=14.5 Hz, 1H), 4.13 (m, 1H), 4.08 (d, J=14.5 Hz, 3.93 (d, J=13.9
Hz, 1H), 3.63 (s, 1H), 3.60 (s, 3H), 3.09-2.76 (m, 5H), 2.34 (s,
3H), 2.18 (s, 3H), 0.58 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta.
177.6, 172.3, 166.8, 159.9, 159.0, 142.2, 141.5, 138.7, 137.5,
131.6, 130.4, 130.13, 130.10, 128.9, 128.7, 127.7, 127.4, 126.0,
125.7, 117.8, 79.3, 73.8, 68.5, 62.9, 62.4, 58.5, 52.7, 44.3, 40.8,
34.9, 26.7, 11.4, 10.7; MS (m/z 698, M+H.sup.+).
Example 35
##STR00099##
((1S)-1-{N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[4-((E)-styryl)-benzyl]-hydrazinocarbonyl}-2,2-dimethyl-pr-
opyl)-carbamic acid methyl ester (35)
Compound 35 was prepared according to Method B, using compound 19
(89.5 mg, 0.132 mmol), trans-phenylethenyboronic acid (97.3 mg,
0.658 mmol), Pd(PPh).sub.3Cl.sub.2 (4.56 mg, 0.0065 mmol), 2 M
Na.sub.2CO.sub.3 (aq., 0.197 mL, 0.395 mmol), EtOH (0.4 mL) and DME
(1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-90%
CH.sub.3CN in 0.05% aqueous formic acid) afforded the product (54.4
mg, 59%) as a white solid.
[.alpha.].sub.D.sup.20-68.0.degree. (c 0.81, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3 2:1) .delta. 7.48 (m, 2H),
7.39-6.91 (m, 17H), 6.81 (m, 1H), 5.01 (d, J=4.97 Hz, 1H), 4.20 (d,
J=14.5 Hz, 1H), 4.11 (m, 1H), 4.03 (d, J=14.5 Hz, 1H), 3.88 (d,
J=14.0 Hz, 1H), 3.63 (s, 1H), 3.59 (s, 3H), 3.05-2.74 (m, 5H), 0.59
(s, 9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3 2:1) .delta. 176.9,
171.8, 158.4, 141.3, 140.9, 138.2, 137.7, 137.6, 137.1, 131.3,
129.5, 129.4, 129.1, 129.0, 128.61, 128.56, 128.3, 127.4, 127.2,
127.1, 125.7, 125.2, 78.8, 73.6, 67.9, 62.4, 62.3, 58.1, 52.7,
44.1, 40.3, 34.7, 26.4; MS (m/z 705, M+H.sup.+).
Example 36
##STR00100##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-(4-phenylethynyl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-p-
ropyl}-carbamic acid methyl ester (36)
Compound 36 was prepared according to Method D, using compound 19
(88.4 mg, 0.130 mmol), phenylacetylene (0.0285 mL, 0.260 mmol),
Et.sub.3N (0.181 mL, 1.30 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (4.49
mg, 0.0064 mmol), CuI (2.46 mg, 0.0129 mmol) and DMF (2.1 mL).
RP-LC-MS (35 min gradient of 40-100% CH.sub.3CN in 0.05% aqueous
formic acid) afforded the title compound (20.4 mg, 22%) as a white
solid.
[.alpha.].sub.D.sup.19-58.0.degree. (c 1.3, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD) .delta. 7.59-7.04 (m, 16H), 6.95 (m, 1H),
6.81 (m, 1H), 4.98 (d, J=4.97 Hz, 1H), 4.22 (d, J=14.5, 1H), 4.14
(m, 1H), 4.07 (d, J=14.5, 1H), 3.89 (d, J=14.0, 1H), 3.63 (s, 1H),
3.61 (s, 3H), 3.07-2.77 (m, 5H), 0.62 (s, 9H); .sup.13C NMR
(CD.sub.3OD/CDCl.sub.3 2:1) .delta. 176.7, 171.7, 162.2, 141.1,
140.8, 138.5, 137.0, 132.17, 132.16, 132.07, 131.2, 129.1, 129.0,
128.9, 128.6, 128.5, 127.3, 125.6, 125.0, 124.0, 123.1, 89.7 (2 C),
78.6, 73.5, 68.0, 62.2, 62.1, 58.0, 52.7, 44.0, 40.1, 34.7, 26.4;
MS (m/z 703, M+H.sup.+).
Example 37
##STR00101##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N-(4-pyridin-2-ylethynyl-benzyl)-hydrazinocarbonyl]-2,2-dimet-
hyl-propyl}-carbamic acid methyl ester (37)
Compound 37 was prepared according to Method D, using compound 19
(92.7 mg, 0.136 mmol), 2-(ethynyl)pyridine (0.0280 mL, 0.272 mmol),
Et.sub.3N (0.190 mL, 1.36 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (4.80
mg, 0.0068 mmol), CuI (2.60 mg, 0.0136 mmol) and DMF (2.1 mL).
RP-LC-MS (35 min gradient of 20-100% CH.sub.3CN in 0.05% aqueous
formic acid) afforded the title compound (34.2 mg, 34%) as a white
solid.
[.alpha.].sub.D.sup.19-25.0.degree. (c 0.56, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 8.52 (m, 1H), 7.85 (m, 1H), 7.62
(m, 1H), 7.46-6.90 (m, 13H), 6.78 (m, 1H), 4.97 (d, J=5.10 Hz, 1H),
4.23 (d, J=14.8 Hz, 1H), 4.12 (m, 1H), 4.10 (d, J=14.8 Hz, 1H),
3.89 (d, J=14.1 Hz, 1H), 3.62 (s, 1H). 3.59 (s, 3H), 3.08-2.76 (m,
5H), 0.60 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 177.5, 172.4,
159.0, 150.6, 144.0, 142.1, 141.4, 140.7, 138.7, 137.5, 132.9,
131.6, 129.8, 128.92, 128.88, 128.7, 127.7, 127.5, 126.1, 125.7,
124.7, 122.1, 90.7, 88.7, 79.3, 73.8, 68.5, 62.9, 62.5, 58.5, 52.7,
44.3, 40.8, 34.9, 26.6; MS (m/z 704, M+H.sup.+).
Example 38
##STR00102##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-(4-pyridin-3-ylethynyl-benzyl)-hydrazinocarbonyl]-2,2-dime-
thyl-propyl}-carbamic acid methyl ester (38)
Compound 38 was prepared according to Method D, using compound 19
(85.8 mg, 0.126 mmol), 3-(ethynyl)pyridine (0.0260 mL, 0.252 mmol),
Et.sub.3N (0.176 mL, 1.26 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (4.42
mg, 0.0063 mmol), CuI (2.40 mg, 0.0126 mmol) and DMF (2.1 mL).
RP-LC-MS (35 min gradient of 25-100% CH.sub.3CN in 0.05% aqueous
formic acid) afforded the title compound (40.3 mg, 45%) as a white
solid.
[.alpha.].sub.D.sup.18-24.2.degree. (c 0.94, CH.sub.3OH);
.sup.1H NMR (CD.sub.3OD) .delta. 8.69 (m, 1H), 8.50 (m, 1H), 7.96
(m, 1H), 7.59-6.89 (m, 13H), 6.79 (m, 1H), 4.98 (d, J=5.05 Hz, 1H),
4.24 (d, J=14.6 Hz, 1H), 4.12 (m, 1H), 4.09 (d, J=14.6 Hz, 1H),
3.90 (d, J=14.1 Hz, 1H), 3.63 (s, 1H), 3.60 (s, 3H), 3.08-2.73 (m,
5H), 0.61 (s, 9H); .sup.13C NMR (CD.sub.3OD) .delta. 177.5, 172.4,
159.0, 152.4, 149.1, 142.1, 141.4, 140.5, 140.3, 137.5, 132.6,
131.6, 129.8, 128.92, 128.86, 127.7, 127.5, 126.1, 125.6, 122.6,
93.9, 86.1, 79.3, 73.8, 68.5, 62.9, 62.5, 58.4, 52.7, 44.4, 40.8,
34.9, 26.6 (two aromatic carbon signals overlapping with other
signals); MS (m/z 704, M+H.sup.+).
Example 39
##STR00103##
{(1S)-1-[N'-(Biphenyl-3-yl-methyl)-N'-[(2S)-2-hydroxy-2-((1S,2R)-2-hydroxy-
-indan-1-ylcarbamoyl)-3-phenyl-propyl]-hydrazinocarbonyl]-2,2-dimethyl-pro-
pyl}-carbamic acid methyl ester (39)
The title compound was prepared according to Method B using
compound 26 (80.5 mg, 0.118 mmol), phenylboronic acid (72.5 mg,
0.595 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (6.50 mg, 0.00926 mmol), 2
M Na.sub.2CO.sub.3 (aq., 0.177 mL, 0.354 mmol), DME (1.6 mL) and
EtOH (0.4 mL) affording the product (21.2 mg, 26%) after RP-LC-MS
(35 min gradient of 40-100% CH.sub.3CN in 0.05% aqueous formic
acid) as a white solid.
[.alpha.].sub.D.sup.19-88.0.degree. (c 0.96, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 4:1) .delta. 7.62 (m, 1H),
7.52-7.17 (m, 14H), 7.04-6.87 (m, 2H), 6.53 (m, 1H), 5.00 (d,
J=4.68 Hz, 1H), 4.28 (d, J=14.45 Hz, 1H), 4.10 (m, 1H), 4.06 (d,
J=14.5 Hz, 1H), 3.93 (d, J=14.1 Hz, 1H), 3.58 (m, 4H), 3.03-2.70
(m, 15H), 0.52 (s, 9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3, 4:1)
.delta. 176.9, 171.8, 158.4, 142.1, 141.8, 141.1, 140.8, 138.7,
137.1, 131.3, 129.4, 128.6, 128.4, 128.1, 127.9, 127.77, 127.76,
127.72, 127.42, 127.41, 126.9, 125.6, 125.0, 78.7, 73.5, 68.1,
62.4, 62.3, 58.1, 52.7, 44.1, 40.1, 34.7, 26.4; MS (m/z 680,
M+H.sup.+).
Example 40
##STR00104##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[3-(pyridin-2-yl)-benzyl)]-hydrazinocarbonyl]-2,2-dimethyl-
-propyl}-carbamic acid methyl ester (40)
The title compound was synthesized according to Method A using
compound 26 (80.2 mg, 0.118 mmol),
2-(1,1,1-tributylstannyl)-pyridine (174 mg, 0.474 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (4.50 mg, 0.00641 mmol), CuO (10.5 mg,
0.132 mmol) and DMF (2 mL). RP-LC-MS (35 min gradient of 20-80%
CH.sub.3CN in 0.05% aqueous formic acid) afforded the product (14.1
mg, 18%) as a white solid.
[.alpha.].sub.D.sup.19-59.6.degree. (c 0.94, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 8.53 (m, 1H), 7.84
(m, 1H), 7.79-7.59 (m, 3H), 7.40-7.17 (m, 8H), 7.01 (m, 1H), 6.92
(m, 2H), 6.58 (m, 1H), 5.00 (d, J=5.08 Hz, 1H), 4.27 (d, J=14.5 Hz,
1H), 4.12 (d, J=14.5, 1H), 4.10 (m, 1H), 3.94 (d, J=14.1 Hz, 1H),
3.60 (s, 1H), 3.58 (s, 3H), 3.03-2.71 (m, 5H), 0.51 (s, 9H);
.sup.13C NMR (CD.sub.3OD/CDCl.sub.3, 1:1) 6176.6, 171.7, 158.1,
149.5, 141.0, 140.7, 139.7, 138.7, 138.3, 137.0, 132.6, 131.2,
129.8, 129.5, 128.5, 128.3, 127.7, 127.3, 127.2, 126.9, 125.4,
124.9, 123.1, 122.4, 78.5, 73.4, 67.8, 62.11, 62.08, 57.9, 52.6,
43.9, 40.0, 34.6, 26.3; HRMS (M+H.sup.+): 680.3428,
C.sub.39H.sub.46N.sub.5O.sub.6 requires 680.3448.
Example 41
##STR00105##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[3-(pyridin-3-yl)-benzyl)]-hydrazinocarbonyl]-2,2-dimethyl-
-propyl}-carbamic acid methyl ester (41)
The title compound was synthesized from compound 26 (79.1 mg, 0.116
mmol), 3-(1,1,1-tributylstannyl)-pyridine (175 mg, 0.476 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (4.10 mg, 0.00584 mmol) and CuO (11.0
mg, 0.138 mmol) and DMF (2 mL) as described in Method A. The
product (19.7 mg, 25%) was obtained after purification by RP-LC-MS
(35 min gradient of 10-85% CH.sub.3CN in 0.05% aqueous formic acid)
as a white solid.
[.alpha.].sub.D.sup.19-72.8.degree. (c 1.13, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 8.58 (m, 1H), 8.40
(m, 1H), 7.83 (m, 2H), 7.67-7.16 (m, 9H), 6.98 (m, 1H), 6.85 (m,
2H), 6.45 (m, 1H), 4.96 (d, J=5.08 Hz, 1H), 4.29 (d, J=14.5 Hz,
1H), 4.10 (d, J=14.5, 1H), 4.08 (m, 1H), 3.95 (d, J=14.1 Hz, 1H),
3.58 (m, 4H), 3.03-2.71 (m, 5H), 0.48 (s, 9H); .sup.13C NMR
(CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 176.9, 171.8, 158.3, 148.0,
147.9, 141.3, 140.8, 139.4, 138.0, 137.0, 136.1 (two carbons
according to ghsqc), 131.2, 129.8, 129.1, 128.6, 128.3, 127.9,
127.4, 127.1, 126.7, 125.5, 125.0, 124.9, 78.8, 73.3, 68.1, 62.24,
62.21, 58.0, 52.7, 44.0, 40.2, 34.6, 26.3; HRMS (M+H.sup.+):
680.3458, C.sub.39H.sub.46N.sub.5O.sub.6 requires 680.3448.
Example 42
##STR00106##
((1S)-1-{N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[3-((E)-styryl)-benzyl]-hydrazinocarbonyl}-2,2-dimethyl-pr-
opyl)-carbamic acid methyl ester (42)
Synthesis of the title compound was performed according to Method B
using compound 26 (80.0 mg, 0.117 mmol), trans-phenylethenyboronic
acid (86.9 g, 0.587 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (6.90 g,
0.00983 mmol), 2 M Na.sub.2CO.sub.3 (aq., 0.176 mL, 0.352 mmol),
DME (1.6 mL) and EtOH (0.4 mL). RP-LC-MS (35 min gradient of 0-80%
CH.sub.3CN in 0.05% aqueous formic acid) afforded the product (39.7
mg, 48%) as a white solid.
[.alpha.].sub.D.sup.18-71.0.degree. (c 1.17, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 5:2) .delta. 7.53 (m, 1H),
7.46-7.13 (m, 14H), 7.10-6.93 (m, 4H), 6.75 (m, 1H), 5.00 (d,
J=4.69 Hz, 1H), 4.24 (d, J=14.5 Hz, 1H), 4.11 (m, 1H), 4.05 (d,
J=14.5 Hz, 1H), 3.96 (d, J=14.1 Hz, 1H), 3.60 (m, 4H), 3.04-2.75
(m, 5H), 0.58 (s, 9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3, 5:2)
.delta. 176.7, 171.7, 158.3, 141.0, 140.8, 138.5, 138.3, 138.1,
137.0, 131.3, 129.5, 129.23, 129.19, 129.1, 128.6, 128.5, 128.3,
128.1, 127.6, 127.4, 127.2, 127.1, 126.2, 125.5, 125.0, 73.5, 68.1,
62.3, 62.2, 58.0, 52.7, 44.0, 40.1, 34.7, 26.4 (one aliphatic
carbon signal overlapping with other signal);
MS (m/z 706 .mu.M+H.sup.+).
Example 43
##STR00107##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-(3-phenylethynyl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-p-
ropyl}-carbamic acid methyl ester (43)
Method C was followed using compound 26 (79.2 mg, 0.116 mmol),
phenylacetylene (0.0150 mL, 0.139 mmol), Et.sub.2NH (0.110 mL, 1.01
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (6.10 g, 0.00869 mmol), CuI
(1.90 mg, 0.00998 mmol) and DMF (2 mL). RP-LC-MS (35 min gradient
of 20-90% CH.sub.3CN in 0.05% aqueous formic acid) afforded the
title compound (22.2 mg, 27%) as a white solid.
[.alpha.].sub.D.sup.18-96.6.degree. (c 0.87, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 3:1) .delta. 7.49 (m, 1H),
7.45-7.14 (m, 13H), 7.08 (m, 1H), 7.00 (m, 2H), 6.83 (m, 1H), 5.01
(d, J=4.68 Hz, 1H), 4.22 (d, J=14.5 Hz, 1H), 4.13 (m, 1H), 4.04 (d,
J=14.5 Hz, 1H), 3.91 (d, J=14.1 Hz, 1H), 3.61 (m, 4H), 3.05-2.78
(m, 5H), 0.61 (s, 9H); .sup.13C NMR (CD.sub.3OD/CDCl.sub.3, 3:1)
.delta. 177.1, 172.0, 158.6, 141.4, 140.9, 138.9, 137.2, 132.3,
132.0, 131.40, 131.38, 129.24, 129.18, 129.16, 129.1, 128.7, 128.6,
127.7, 127.5, 125.8, 125.3, 124.4, 124.3, 90.01, 90.03, 78.9, 73.6,
68.4, 62.5, 62.1, 58.1, 52.7, 44.1, 40.4, 34.8, 26.5;
MS (m/z 704, M+H.sup.+).
Example 44
##STR00108##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[3-(pyridin-2-ylethynyl)-benzyl]-hydrazinocarbonyl]-2,2-di-
methyl-propyl}-carbamic acid methyl ester (44)
The title compound was synthesized according to Method C using
compound 26 (79.4 mg, 0.117 mmol), 2-(ethynyl)pyridine (15.3 mg,
0.148 mmol), Et.sub.2NH (0.105 mL, 1.01 mmol)
Pd(PPh.sub.3).sub.2Cl.sub.2 (6.50 mg, 0.00926 mmol), CuI (1.50 mg,
0.00788 mmol) and DMF (2 mL). RP-LC-MS (35 min gradient of 0-100%
CH.sub.3CN in 0.05% aqueous formic acid) gave the product (15.9 mg,
19%) as a white solid.
[.alpha.].sub.D.sup.19-367.degree. (c 0.60, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 8.48 (m, 1H), 7.73
(m, 1H), 7.56-7.15 (m, 1H), 7.08-6.92 (m, 3H), 6.82 (m, 1H), 5.01
(d, J=4.68 Hz, 1H), 4.19 (d, J=14.7 Hz, 1H), 4.09 (m, 1H), 4.02 (d,
J=14.7 Hz, 1H), 3.92 (d, J=14.1 Hz, 1H), 3.60 (s, 3H), 3.59 (s,
1H), 3.00-2.74 (m, 5H), 0.59 (s, 9H); .sup.13C NMR
(CD.sub.3OD/CDCl.sub.3, 1:1) .delta. 176.3, 171.4, 158.0, 149.8,
143.4, 140.7, 140.5, 138.6, 137.6, 136.8, 132.2, 131.6, 131.8,
129.8, 129.0, 128.4, 128.3, 128.1, 127.3, 127.2, 125.4, 124.8,
123.8, 122.6, 90.4, 88.4, 78.6, 73.4, 68.0, 61.9, 61.6, 57.8, 52.7,
43.8, 39.7, 34.6, 26.2;
HRMS (M+H.sup.+): 704.3438, C.sub.41H.sub.46N.sub.5O.sub.6 required
704.3448.
Example 45
##STR00109##
{(1S)-1-[N'-[(2S)-2-Hydroxy-2-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-3-ph-
enyl-propyl]-N'-[3-(pyridin-3-ylethynyl)-benzyl]-hydrazinocarbonyl]-2,2-di-
methyl-propyl}-carbamic acid methyl ester hydrochloride (45)
The title compound was synthesized according to Method C using
compound 26 (89.5 mg, 0.131 mmol), 3-(ethynyl)pyridine (16.3 mg,
0.158 mmol), Et.sub.2NH (0.118 mL, 1.14 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (7.70 mg, 0.0110 mmol), CuI (1.80,
0.00945 mmol) and DMF (2 mL). The crude product was purified by
RP-LC-MS (35 min gradient of 10-85% CH.sub.3CN in 0.05% aqueous
formic acid). The HCl-salt of the product was made by dissolving
the product in CH.sub.2Cl.sub.2 followed by addition of HCl in
ether until all product had precipitated. After evaporation the
salt was dissolved in CH.sub.3CN and H.sub.2O, and subsequently
freeze dried which gave the title compound (21.6 mg, 23%) as a
white solid.
[.alpha.]D.sup.19-65.7.degree. (c 1.15, CHCl.sub.3);
.sup.1H NMR (CD.sub.3OD/CDCl.sub.3, 9:1) .delta. 8.25 (m, 1H), 7.61
(m, 1H), 7.52-7.17 (m, 11H), 7.10-6.91 (m, 3H), 6.74 (m, 1H), 5.00
(d, J=5.07 Hz, 1H), 4.23 (d, J=14.5 Hz, 1H), 4.14 (m, 1H), 4.08 (d,
J=14.5 Hz, 1H), 3.93 (d, J=13.7 Hz, 1H), 3.62 (s, 1H), 3.60 (s,
3H), 3.05-2.77 (m, 5H), 0.59 (m, 9H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 174.6, 170.1, 156.5, 149.8, 147.2, 142.1, 140.5, 140.4,
138.7, 136.4, 130.9, 130.2, 130.1, 129.1, 128.3, 127.6, 127.0,
126.2, 125.9, 124.7, 124.0, 121.1, (2 aromatic carbon signals
overlapping with other signals), 93.4, 85.1, 79.2, 77.5, 71.8,
67.6, 61.3, 60.7, 56.4, 51.5, 42.9, 33.5, 26.1;
HRMS (M+H.sup.+): 704.3468, C.sub.41H.sub.46N.sub.5O.sub.6 required
704.3448.
Example 46
##STR00110##
(R)-2-Benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl--
8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxybutan-1-one
(46)
To a cooled (0.degree. C.) solution of
(R)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-N-((1S,2R)-2-hy-
droxy-indan-1-yl)-butyramide (22) (0.4 g, 0.69 mmol) and pyridinium
p-toluenesulphonic acid (15 mg, 0.059 mmol) in dry dichloromethane
(25 mL), 2-methoxypropene (0.5 g, 6.9 mmol) was added and stirred
for 6 h at the same temperature. Saturated NaHCO.sub.3 solution was
added and the organic layer was washed with sat. NaHCO.sub.3,
brine, dried over anhydrous MgSO.sub.4 and evaporated under reduced
pressure. The title compound (0.325 g) was used without further
purification in the next step.
MS (ESI.sup.+): 620 (M.sup.+).
Example 47
##STR00111##
(R)-2-Benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazo-
l-3-yl)-2,4-dihydroxy-butan-1-one (47)
TBAF (0.274 g, 1.05 mmol, 1M in THF) was added to a solution of
(R)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-1-((3aS,8aR)-2,2-dimethyl-
-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-butan-1-one
(46) (0.325 g, 0.52 mmol) in THF (20 mL) at room temperature and
stirred for 3 h. The solvent was evaporated and the residue
dissolved in dichloromethane and washed with water and brine, dried
and evaporated. The product was purified by flash chromatography
using petroleum ether:acetone (4:1) which gave 0.140 g of the title
compound in 53% yield from two steps.
MS (ESI.sup.+): m/z: 382 (M.sup.++1);
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.62 (m, 1H), 7.34-7.28
(m, 5H), 7.16-7.12 (m, 3H), 5.20 (m, 1H), 4.02 (m, 1H), 3.91-3.85
(m, 2H), 3.12 (d, J=13.20 Hz, 1H), 2.98 (d, J=13.20 Hz, 1H),
2.82-2.68 (m, 2H), 2.58 (m, 1H), 2.00 (m, 1H), 1.56 (s, 3H), 1.13
(s, 3H); .sup.13C NMR (CD.sub.3OD, 100 MHz): .delta. 171.6, 142.4,
140.5, 136.6, 131.0, 127.8, 127.4, 126.8, 126.4, 126.2, 124.7,
98.0, 80.7, 79.6, 67.2, 59.0, 43.1, 35.1, 25.7, 23.9.
Example 48
##STR00112##
(R)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3
aH-indeno[1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyraldehyde (48)
A solution of (R)-2-benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3
aH-indeno[1,2-d]oxazol-3-yl)-2,4-dihydroxybutan-1-one (47) (0.12 g,
0.31 mmol) in dry CH.sub.2Cl.sub.2 (5 mL) was added over 1 min to a
stirred solution of Dess-Martin periodinate (0.146 g, 0.35 mmol) in
dry CH.sub.2Cl.sub.2 (10 mL). After 30 min the homogeneous mixture
was diluted with ether and poured into cold saturated NaHCO.sub.3
(10 mL) containing Na.sub.2S.sub.2O.sub.3 (2.2 g). The organic
layer was washed with aqueous saturated NaHCO.sub.3, brine and
dried (MgSO.sub.4). The solvents were evaporated below 20.degree.
C. to give the title compound (0.086 g, 72%). The residue was
immediately used for the next step.
MS (ESI.sup.+): 380 (M.sup.++1).
Example 49
##STR00113##
((S)-1-{N'-(4-Bromo-benzyl)-N'-[(R)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan-1-
-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-carb-
amic acid methyl ester (49)
Method B:
(R)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[-
1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyraldehyde (48) (0.086 g,
0.23 mmol) and
{(S)-1-[N'-(4-Bromo-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-c-
arbamic acid methyl ester (0.084 g, 0.23 mmol) in dry THF (10.0 mL)
was added acetic acid (0.027 g, 0.45 mmol) and stirred for 10 min
and then Na(OAc).sub.3BH (0.144 g, 0.68 mmol) was added and stirred
overnight. The reaction mixture was quenched with water and
evaporated. The residue was dissolved in dichloromethane (20.0 mL)
and washed with water, brine and trifluoroacetic acid (1.0 mL) was
added and stirred the organic layer for 20 min. The mixture was
evaporated and washed successively with aqueous NaHCO.sub.3, water,
brine and dried. The product was purified on silica gel flash
chromatography using acetone:pet.ether (1:3) to yield 0.057 g (36%)
of the title compound.
MS (ESI.sup.+): m/z: 695, 697 (M.sup.+);
.sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.40-7.24 (m, 11H),
7.20-7.10 (m, 2H), 7.00 (m, 1H), 6.24 (m, 1H), 5.18 (m, 1H), 4.42
(m, 1H), 3.85 (s, 1H), 3.66 (s, 3H), 3.12-2.82 (m, 6H), 2.62 (s,
1H), 2.20 (m, 1H), 1.90 (m, 1H), 0.88 (s, 9H); .sup.13C NMR
(CD.sub.3OD, 100 MHz): .delta. 176.2, 171.1, 159.0, 140.7, 140.2,
136.8, 131.5, 130.7, 127.8, 127.5, 124.7, 124.0, 121.2, 79.4, 73.1,
61.7, 57.0, 54.8, 51.6, 45.9, 39.5, 34.5, 33.4, 28.3, 25.6.
Example 50
##STR00114##
{(S)-1-[N'-[(S)-3-Hydroxy-3-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-4-phen-
yl-butyl]-N'-(4-pyridin-3-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propy-
l}-carbamic acid methyl ester (50)
Pd(PPh.sub.3).sub.2Cl.sub.2 (3.84 mg, 0.0054 mmol) was added to a
solution of
((S)-1-{N-(4-Bromo-benzyl)-N'-[(S)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan-1-
-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-carb-
amic acid methyl ester (22) (75 mg, 0.108 mmol),
3-(1,1,1-tri-n-butylstannyl)pyridine (159 mg, 0.431 mmol) and CuO
(8.6 mg, 0.108 mmol) in DMF (2.0 mL) and stirred in a heavy-walled
Smith process vial at 120.degree. C. 50 min in the microwave
cavity. The mixture was diluted with CH.sub.2Cl.sub.2 (20.0 mL) and
washed with aq. saturated NaHCO.sub.3 (3.times.15.0 mL). The
organic layer was dried (MgSO.sub.4) and evaporated. The residue
was re-dissolved in CH.sub.3CN (50.0 mL) and washed with isohexane
(3.times.20.0 mL). The acetonitrile phase was evaporated and the
crude product was purified using RP-LC-MS (45 min gradient of
15-70% CH.sub.3CN in 0.05% aqueous formic acid) which gave the
title product (23.1 mg, 31%) as a white solid.
MS (ESI.sup.+): m/z: 694 (M.sup.+);
.sup.1H NMR (CD.sub.3OD 400 MHz): .delta. 8.66 (m, 1H), 8.45 (m,
1H), 8.00 (m, 1H), 7.52-7.44 (m, 6H), 7.30-7.04 (m, 9H), 5.04 (m,
1H), 4.24 (m, 1H), 3.82 (m, 2H), 3.68 (s, 1H), 3.60 (s, 3H),
3.10-2.78 (m, 6H), 2.62 (s, 1H), 2.20 (m, 1H), 1.96 (m, 1H), 0.78
(s, 9H); .sup.13C NMR (CD.sub.3OD, 100 MHz): .delta. 176.9, 171.1,
157.8, 147.8, 147.0, 141.3, 140.3, 137.0, 136.8, 135.2, 130.5,
130.0, 127.6, 126.8, 126.5, 126.3, 124.9, 124.1, 78.7, 72.5, 61.9,
61.7, 57.2, 53.6, 51.5, 39.6, 34.3, 33.5, 28.3, 25.7
Example 51
##STR00115##
{(S)-1-[N'-[(S)-3-Hydroxy-3-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-4-phen-
yl-butyl]-N'-(4-pyridin-2-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propy-
l}-carbamic acid methyl ester (51)
Pd(PPh.sub.3).sub.2Cl.sub.2 (4.61 mg, 0.0065 mmol) was added to a
solution of
((S)-1-{N'-(4-Bromo-benzyl)-N'-[(S)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan--
1-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-car-
bamic acid methyl ester (22) (90 mg, 0.129 mmol),
2-(1,1,1-tri-n-butylstannyl)pyridine (191 mg, 0.51 mmol) and CuO
(10.3 mg, 0.129 mmol) in DMF (2.0 mL) and stirred in a heavy-walled
Smith process vial at 120.degree. C. 50 min in the microwave
cavity. The mixture was diluted with CH.sub.2Cl.sub.2 (25.0 mL) and
washed with aq. saturated NaHCO.sub.3 (3.times.15.0 mL) The organic
layer was dried (MgSO.sub.4) and evaporated. The residue was
re-dissolved in CH.sub.3CN (60.0 mL) and washed with isohexane
(3.times.20.0 mL). The acetonitrile phase was evaporated and the
crude product was purified using RP-LC-MS (45 min gradient of
15-70% CH.sub.3CN in 0.05% aqueous formic acid) which gave the
title product (36.2 mg, 40%) as a white solid.
MS (ESI.sup.+): m/z: 694 (M.sup.+);
.sup.1H NMR (CD.sub.3OD 400 MHz): .delta. 8.56 (m, 1H), 7.82 (m,
1H), 7.72-7.60 (m, 4H), 7.54 (m, 1H), 7.44 (m, 1H), 7.34-7.16 (m,
6H), 7.06-7.00 (m, 3H), 6.96 (m, 1H), 4.96 (m, 1H), 4.16 (m, 1H),
3.82 (m, 2H), 3.70 (m, 1H), 3.60 (s, 3H), 3.08-2.78 (m, 6H), 2.10
(m, 1H), 1.94 (m, 1H), 0.78 (s, 9H); .sup.13C NMR (CD.sub.3OD, 100
MHz): .delta. 176.9, 171.5, 158.2, 157.7, 149.1, 141.5, 140.5,
138.6, 138.1, 138.0, 137.2, 132.9, 132.3, 132.2, 130.8, 129.9,
129.2, 129.1, 127.9, 127.3, 126.9, 126.6, 125.0, 124.5, 122.8,
121.7, 79.3, 73.1, 62.3, 57.7, 53.6, 51.9, 46.6, 39.8, 34.5, 33.9,
26.1.
Example 52
##STR00116##
(2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-
-butyramide (52S)
3-Benzyl-3-hydroxy-dihydro-furan-2-one (21c) (0.961 g, 5.00 mmol),
H-tLeu-NHMe (1.80 g, 12.5 mmol) and 2-pyridone (0.476 g, 5.0 mmol)
was suspended in 10 mL 1,2-dichloroethane in a reaction tube. The
vessel was sealed with a screw cap and heated in a metal heating
block at 80.degree. C. for 24 h. The solvent was evaporated and the
residue was re-dissolved in the least amount of 25% acetonitrile in
water and the mixture was purified and the diastereomers separated
by column chromatography using RP(C-18)-silica and a manual 10-50%
acetonitrile in water gradient (with 0.05% HCOOH). The resulting
fractions were analyzed by analytical RP-LC-MS and pure fractions
pooled together and the solvent was evaporated to give
(2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydrox-
y-butyramide (0.424 g, 25%) and
(2R)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydrox-
y-butyramide (0.631 g, 38%).
MS (ESI.sup.+): m/z 337 (M+H).sup.+;
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.20-7.14 (m, 5H), 4.05
(s, 1H), 3.82-3.68 (m, 2H), 3.03 (d, J=13.4 Hz, 1H), 2.85 (d,
J=13.4 Hz, 1H), 2.85 (s, 3H), 2.29-2.21 (m, 2H), 1.98-1.89 (m, 2H),
0.93 (s, 9H). .sup.13C NMR (CD.sub.3OD, 100.5 MHz): .delta. 176.2,
172.2, 137.3, 131.3, 128.8, 127.4, 79.6, 61.5, 59.6, 47.1, 41.7,
35.7, 27.0, 26.0.
Example 53
##STR00117##
(1-{N'-(4-Bromobenzyl)-N'-[3-(2,2-dimethyl-1-methylcarbamoyl-propylcarbamo-
yl)-3-hydroxy-4-phenyl-butyl]-hydrazinocarbonyl}2,2-dimethylpropyl)carbami-
c acid methyl ester (53)
A mixture of
(2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydrox-
y-butyramide (52S) (0.337 g, 1.00 mmol), IBX (0.560 g, 2.0 mmol)
and 10 mL 1,2-dichloroethane in a reaction vial sealed with a screw
cap was heated at 80.degree. C. for 2 h. The resulting suspension
was transferred to a 20 mL syringe and filtered through a syringe
filter into a solution of hydrazide (9) (0.372 g, 1.00 mmol) in 15
mL DCE in a flame dried 50 mL round-bottom flask equipped with a
septum. To this was added acetic acid (0.12 mL 2.0 mmol), mixture
was stirred for 10 min and then sodium triacetoxyborohydride (0.636
g, 3.0 mmol) was added. The septum-sealed flask was flushed with
nitrogen and the reaction was stirred at room temperature for 24 h.
The reaction was quenched by addition of water and volatiles were
evaporated. The residue was dissolved in 50% MeCN/water and
purified by preparative RP-LC-MS (repeated 1 mL injections) to give
0.191 g of the title compound (28% yield).
MS (ESI.sup.+): m/z 690, 692 (M+H).sup.+
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 7.47 (AA' of AA'XX'
system, 2H), 7.33 (XX' of AA'XX' system, 2H), 7.19-7.16 (m, 5H),
4.02 (s, 1H), 3.85 (s, 2H), 3.75 (s, 1H), 3.68 (s, 3H), 3.04-2.87
(m, 3H), 2.77 (d, J=13.2 Hz, 1H), 2.61 (s, 3H), 2.23-2.13 (m, 1H),
2.02-1.90 (m, 1H), 0.89 (s, 9H), 0.80 (s, 9H).
.sup.13C NMR (CD.sub.3OD, 100.5 MHz): .delta. 176.5, 172.3, 172.1,
158.9, 137.5, 137.2, 132.3, 131.4, 128.7, 127.3, 122.4, 79.7, 63.0,
62.4, 61.5, 54.8, 52.8, 47.1, 35.7, 35.6, 34.7, 27.1, 26.9,
26.0.
Example 54
##STR00118##
{1-[N'-(3-(2,2-Dimethyl-1-methylcarbamoyl-propylcarbamoyl)-3-hydroxy-4-phe-
nyl-butyl]-N'-(4-pyridin-3-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-prop-
yl}carbamic acid methyl ester (54)
A mixture of compound (53) (69 mg, 0.10 mmol), 3-pyridylboronic
acid (37 mg, 0.30 mmol), Pd(OAc).sub.2 (1.1 mg, 0.0050 mmol),
[(t-Bu).sub.3PH]BF.sub.4 (3.0 mg, 0.010 mmol) and K.sub.2CO.sub.3
(41.5 mg, 0.30 mmol), H.sub.2O (0.30 mL) and 1,2-dimethoxyethane
(1.0 mL) in a 2.0 mL microwave vial was irradiated to 80.degree. C.
for 20 min. The reaction mixture was filtered through celite and
the solvent evaporated under reduced pressure. The residue was
purified by preparative RP-LC-MS which gave 30.1 mg of the title
compound (44% yield) as a colorless solid.
MS (ESI.sup.+): m/z 690 (M+H).sup.+
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. 8.78 (m, 1H), 8.54 (m,
1H), 8.07 (m, 1H), 7.65-7.51 (m, 5H), 7.27-7.15 (m, 5H), 4.03-3.89
(m, 3H), 3.77 (s, 1H), 3.62 (s, 3H), 3.08-2.92 (m, 3H), 2.76 (d,
J=13.2 Hz, 1H), 2.61 (s, 3H), 2.24-2.15 (m, 1H), 2.04-1.93 (m, 1H),
0.89 (s, 9H), 0.79 (s, 9H). .sup.13C NMR (CD.sub.3OD, 100.5 MHz):
.delta. 176.6, 172.3, 172.1, 159.0, 148.7, 148.2, 138.4, 138.3,
137.9, 137.6, 136.6, 136.5, 131.4, 128.7, 128.1, 127.3, 125.5,
79.8, 63.1, 62.9, 61.6, 54.8, 52.7, 47.0, 35.7, 35.6, 34.8, 27.1,
26.9, 26.0.
Example 55
##STR00119##
{1-[N'-[3-Hydroxy-3-(2-hydroxy-indan-1-ylcarbamoyl)-4-phenyl-butyl]-N'-(4--
pyridin-3-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic
acid methyl ester (55)
Pd(PPh.sub.3).sub.2Cl.sub.2 (5.05 mg, 0.0072 mmol) was added to a
solution of
((S)-1-{N'-(4-Bromo-benzyl)-N'-[(S)-3-hydroxy-3-((1S,2R)-2-hydroxy-indan--
1-ylcarbamoyl)-4-phenyl-butyl]-hydrazinocarbonyl}-2,2-dimethyl-propyl)-car-
bamic acid methyl ester (12) (100 mg, 0.143 mmol),
pyridine-4-boronic acid (71.0 mg, 0.575 mmol), 2 M
aq.Na.sub.2CO.sub.3 (0.215 mL, 0.432 mmol), EtOH (0.4 mL) and DME
(1.6 mL) and stirred in a heavy-walled Smith process vial at
120.degree. C. for 30 min in the microwave cavity. Five drops of
formic acid were added to the mixture and then the solvent was
evaporated. The crude product was purified using RP-LC-MS (40 min
gradient of 15-85% CH.sub.3CN in 0.05% aqueous formic acid) yielded
the product (35.3 mg, 35%) as a white solid
MS (ESI.sup.+): m/z: 694 (M.sup.+)
.sup.1H NMR (CD.sub.3OD 400 MHz): .delta. 8.52 (m, 2H), 7.57 (m,
4H), 7.46 (m, 2H), 7.29-7.02 (m, 9H), 5.04 (d, J=14.6 Hz, 1H), 4.23
(m, 1H), 3.81 (m, 2H), 3.65 (m, 1H), 3.58 (s, 3H), 3.07-2.78 (m,
6H), 2.20 (m, 1H), 1.94 (m, 1H), 0.69 (s, 9H).
Example 56
##STR00120##
(S)-5-Benzyl-2,2-dimethyl-[1,3]dioxolan-4-one (56)
A solution of (S)-2-Hydroxy-3-phenyl-propionic acid (1.662 g, 10.0
mmol), 2,2-dimethoxypropane (8.328 g, 80.0 mmol) and PPTSA (1.257
g, 5.0 mmol) in chloroform was stirred at 70.degree. C. for one
hour, concentrated, dissolved in dichloromethane and purified on
silica gel with 10% EtOAc-PE which gave the title compound (2.010
g, 97%) as a white solid.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.37 (s, 3H), 1.50 (s,
3H), 3.05 (dd, J=14.4, 6.4 Hz, 1H), 3.20 (dd, J=14.4, 4.4 Hz, 1H),
4.66 (dd, J=6.4, 4.4 Hz, 1H), 7.20-7.40 (m, 5H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 26.4, 27.2, 37.9, 75.3, 111.1, 127.3,
128.6, 130.1, 136.0, 172.7.
Example 57
##STR00121##
3-(4-Benzyl-2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-propionic acid
methyl ester (57)
To a solution of compound 56 (3.180 g, 15.42 mmol) in THF was added
9.42 mL LDA (1.8 M in THF, 16.96 mmol) at -78.degree. C. Methyl
acrylate (1.460 g, 16.96 mmol) was added to the solution at
-78.degree. C. after 15 min. After 1 h the reaction was quenched
with saturated NH.sub.4Cl aqueous solution, extracted with EtOAc
3.times.30 mL, dried with MgSO.sub.4 and purified on silica gel
with 8-17% EtOAc-PE which gave the title compound (2.418 g, 54%) as
colorless oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95 (s, 3H), 1.51 (s,
3H), 2.15 (t, J=8.0 Hz, 2H), 2.36-2.62 (m, 2H), 2.92 (d, J=13.6 Hz,
1H), 3.10 (d, J=13.6 Hz, 1H), 3.67 (s, 3H), 7.15-7.30 (m, 5H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 27.7, 28.8, 28.9, 33.1,
42.5, 52.1, 83.3, 110.4, 127.5, 128.6, 131.1, 135.1, 173.1,
174.1.
Example 58
##STR00122##
(R)-2-Benzyl-5-oxo-tetrahydro-furan-2-carboxylic acid
((1S,2R)-2-hydroxy-indan-1-yl)-amide (58a)
A solution of compound 57 (2.418 g, 8.272 mmol) in 6 mL
TFA\H.sub.2O (6:1) was stirred at 80.degree. C. overnight. The
solution was concentrated, dissolved in ethyl acetate and
concentrated again for a couple times to get rid of TFA. The
afforded residue was dried with vacuum until the raw product
solidified. (1S,2R)-(-)-cis-1-Amino-2-indanol (1.234 g, 8.272
mmol), EDAC (1.744 g, 9.099 mmol), HOBt (1.229 g, 9.099 mmol) and
60 mL dry dichloromethane were added. The mixture was stirred for
one hour at room temperature. The reaction was quenched with 30 mL
water, filtered and extracted with 2.times.30 mL dichloromethane.
The combined dichloromethane layers were concentrated and the
residue was purified by column chromatography on silica gel eluted
with MeOH--CH.sub.2Cl.sub.2 which gave the title compound (1.206 g,
41%) as a white solid. The other isomer (58b) eluted slower from
the column. The absolute configuration of the title compound was
confirmed by X-ray.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.93 (d, J=4.4 Hz, 1H,
OH), 2.32-2.48 (m, 2H), 2.50-2.64 (m, 1H), 2.76-2.86 (m, 2H), 3.04
(dd, J=16.4, 5.2 Hz, 1H), 3.13 (d, J=14.0 Hz, 1H), 3.36 (d, J=14.0
Hz, 1H), 4.18-4.26 (m, 1H), 5.23 (dd, J=8.8, 4.8 Hz, 1H), 6.68 (d,
J=8.8 Hz, 1H), 7.02-7.08 (m, 1H), 7.14-7.24 (m, 3H), 7.28-7.38 (m,
5H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 28.1, 31.0, 39.2,
44.2, 57.4, 73.0, 88.3, 123.7, 125.2, 127.1, 127.6, 128.3, 128.5,
130.5, 134.8, 139.4, 140.1, 171.4, 175.0.
Example 59
##STR00123##
(R)-2-Benzyl-2-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-pentanoic
acid
[(1S,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-amide
(59)
To a solution of compound 58 (1.206 g, 3.432 mmol) and
triethylamine (1.042 g, 10.30 mmol) in dichloromethane was added
TBDMS-OTf (1.3606 g, 5.148 mmol) at 0.degree. C. and the reaction
mixture was stirred at room temperature for one hour. The solution
was concentrated, extracted with diethyl ether\water. The ether
layer was dried with MgSO.sub.4, and filtered. LiBH.sub.4 (223.8
mg, 10.30 mmol) was added to the ether solution at room
temperature. After stirring for one hour, the reaction mixture was
filtered and the resulting solution was concentrated which gave a
crude intermediate. Pyridine (15 mL) and 0.845 mL PvCl (0.828 g,
6.864 mmol) were added to the afforded crude intermediate and the
solution was stirred overnight. The reaction was quenched with
saturated NH.sub.4Cl aqueous solution, extracted with ether, dried
with MgSO.sub.4, concentrated, purified on silica gel eluted with
EtOAc-PE. All fractions with MS 554 (M.sup.++1) fragment were
collected and concentrated which gave 1.243 g intermediate. The
intermediate (1.243 g, 2.245 mmol), and 937.4 .mu.L TEA (0.6815 g,
6.734 mmol) were dissolved in 15 mL DCM, and TBDMS-OTf (0.8899 g,
3.367 mmol) was added at 0.degree. C. The solution was stirred for
one hour at room temperature and then concentrated and extracted
with diethyl ether\water. The ether layer was dried with
MgSO.sub.4, filtered and LiBH.sub.4 (146.3 mg, 6.734 mmol) was
added to the ether solution at room temperature. After another 1 h
the mixture was filtered, concentrated and purified with 20%-50%
EtOAc-PE which gave the title compound (783.2 mg, 39%) as colorless
oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.00 (s 3H), 0.01 (s,
3H), 0.05 (s, 3H), 0.08 (s, 3H), 0.75 (s, 9H), 0.81 (s, 9H),
1.04-1.28 (m, 1H), 1.48-1.64 (m, 2H), 1.75 (Br s, 1H), 1.92-2.06
(m, 1H), 2.83 (dd, J=15.6, 6.0 Hz, 1H), 2.91 (d, J=14.0 Hz, 1H),
2.99 (dd, J=15.6, 6.0 Hz, 1H), 3.12 (d, J=14.0 Hz, 1H), 3.26-3.42
(m, 2H), 4.54-4.62 (m, 1H), 5.13 (dd, J=8.0, 6.0 Hz, 1H), 7.05-7.20
(m, 8H), 7.30-7.40 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 4.7, -4.3, -2.0, -1.5, 18.5, 18.7, 26.2, 26.4, 27.1, 35.0,
39.9, 47.5, 56.6, 62.3, 74.1, 82.6, 124.9, 125.7, 126.7, 126.9,
128.0, 128.2, 130.4, 136.5, 139.6, 141.8, 174.4.
Example 60
##STR00124##
[(S)-1-(N'-(4-Bromo-benzyl)-N'-{(R)-4-(tert-butyl-dimethyl-silanyloxy)-4-[-
(1S,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylcarbamoyl]-5-phenyl-p-
entyl}-hydrazinocarbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl
ester (60)
To a mixture of compound 59 (412.9 mg, 0.7070 mmol) and Dess-Martin
periodinane (314.9 mg, 0.7424 mmol) was added 15 mL dry
dichloromethane. The mixture was stirred at room temperature for 1
h, then concentrated, dissolved in 15 mL ether and washed with 15
mL water. The water phase was extracted with ether 2.times.15 mL.
The ether layer was dried with MgSO.sub.4, filtered and
concentrated. The residue was dissolved in THF (20 ml) and
{(S)-1-[N-(4-Bromo-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbam-
ic acid methyl ester (263.2 mg, 0.7070 mmol) was added. To the
solution was then added acetic acid (85.0 mg, 1.414 mmol) and the
solution was stirred at room temperature. After 15 min,
Na(OAc).sub.3BH (599.3 mg, 2.828 mmol) was added and the stirring
was continued for another 2 h at room temperature. The reaction was
quenched with saturated NH.sub.4Cl aqueous solution, extracted with
dichloromethane 3.times.20 mL, dried with MgSO.sub.4, concentrated
and purified on silica gel eluted with 20-40% EtOAc-PE which gave
the title compound (300.0 mg, 45%) as white solid. 165 mg Of
compound 59 was recovered.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.05 (s 3H), 0.06 (s,
3H), 0.10 (s, 3H), 0.11 (s, 3H), 0.806 (s, 9H), 0.812 (s, 9H), 0.90
(s, 9H), 1.25-1.40 (m, 1H), 1.45-1.65 (m, 2H), 1.95-2.12 (m, 1H),
2.55-2.70 (m, 1H), 2.80-3.00 (m, 3H), 3.07 (dd, J=15.6, 6.0 Hz,
1H), 3.12 (d, J=13.6 Hz, 1H), 3.50-3.65 (m, 4H), 3.75-3.90 (m, 2H),
4.60-4.70 (m, 1H), 5.15-5.25 (m, 1H), 5.33 (d, J=9.2 Hz, 1H), 6.77
(s, 1H), 7.06-7.28 (m, 10H), 7.34-7.46 (m, 4H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. -4.7, -4.3, -1.9, -1.6, 18.5, 18.6,
21.8, 26.1, 26.3, 26.4, 34.4, 36.9, 39.9, 46.7, 52.4, 55.7, 56.5,
59.4, 61.2, 74.2, 82.7, 121.2, 124.9, 125.9, 126.6, 126.8, 128.0,
128.2, 130.4, 130.9, 131.3, 136.5, 136.6, 139.7, 141.9, 156.8,
169.7, 174.2.
Example 61
##STR00125##
{(S)-1-[N'-[(R)-4-Hydroxy-4-((1S,2R)-2-hydroxy-indan-1-yl]carbamoyl)-5-phe-
nyl-pentyl]-N'-(4-pyridin-4-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-pro-
pyl}-carbamic acid methyl ester (61)
Compound 60 (100.0 mg, 0.1066 mmol), 4-pyridinylbronic acid (39.2
mg, 0.3198 mmol), palladacycle (5.0 mg, 0.00533 mmol),
HP(t-Bu).sub.3BF.sub.4 (3.1 mg, 0.01066 mmol), K.sub.2CO.sub.3
(44.2 mg, 0.3198 mmol), DME (1.0 mL), H.sub.2O (0.3 mL) were added
to a 2-5 mL vial. The mixture was irradiated under microwaves at
120.degree. C. for 20 min. The mixture was then extracted with
ethyl acetate. The organic layer was dried with MgSO.sub.4 and
concentrated. To the afforded residue was added TBAF (1.06 mL) in
THF (1.066 mmol) and the solution was stirred at room temperature
overnight. Water (10 mL) was added to the solution which was then
extracted with dichloromethane, and the organic phase was dried
with MgSO.sub.4 and concentrated. The residue was purified on
silica gel with 1%-5% MeOH--CH.sub.2Cl.sub.2 which gave the title
compound (52.9 mg, 70%) as a white solid.
.sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 0.75 (s, 9H), 1.56-1.70
(m, 1H), 1.70-1.86 (m, 2H), 2.03-2.16 (m, 1H), 2.74-2.94 (m, 4H),
3.01-3.14 (m, 2H), 3.46 (s, 3H), 3.70 (s, 1H), 3.88-4.00 (m, 2H),
4.16-4.22 (m, 1H), 5.09 (d, J=4.8 Hz, 1H), 7.10-7.30 (m, 9H),
7.50-7.70 (m, 6H), 8.50-8.60 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 21.4, 25.7, 33.7, 36.6, 39.7, 45.8, 51.5, 57.1, 57.6,
61.2, 61.8, 72.8, 78.4, 105.0, 121.8, 124.2, 125.0, 126.3, 126.65,
126.68, 127.62, 127.67, 130.3, 130.5, 136.6, 137.0, 139.0, 140.4,
141.3, 149.4, 157.7, 170.7, 176.1.
Example 62
##STR00126##
{(S)-1-[N'-[(R)-4-Hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phen-
yl-pentyl]-N'-(4-pyridin-3-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-prop-
yl}-carbamic acid methyl ester (62) (AHA-625)
Compound 60 (100.0 mg, 0.1066 mmol), 3-pyridinylbronic acid (39.2
mg, 0.3198 mmol), palladacycle (5.0 mg, 0.00533 mmol),
HP(t-Bu).sub.3BF.sub.4 (3.1 mg, 0.01066 mmol), K.sub.2CO.sub.3
(44.2 mg, 0.3198 mmol), 1.0 mL DME, 0.3 mL H.sub.2O were added to a
2-5 mL vial. The mixture was irradiated under microwaves at
120.degree. C. for 20 min. The mixture was then extracted with
ethyl acetate. The organic layer was dried with MgSO.sub.4 and
concentrated.
To the afforded residue was added TBAF (1.06 mL) in THF (1.066
mmol) and the solution was stirred at room temperature overnight.
Water (10 mL) was added to the solution which was then extracted
with dichloromethane, and the organic phase was dried with
MgSO.sub.4 and concentrated. The residue was purified on silica gel
with 1%-5% MeOH--CH.sub.2Cl.sub.2 which gave the title compound
(60.5 mg, 80%) as a white solid.
.sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 0.76 (s, 9H), 1.56-1.71
(m, 1H), 1.71-1.86 (m, 2H), 2.04-2.16 (m, 1H), 2.74-2.95 (m, 4H),
3.00-3.14 (m, 2H), 3.46 (s, 3H), 3.71 (s, 1H), 3.88-3.98 (m, 2H),
4.16-4.22 (m, 1H), 5.10 (d, J=4.8 Hz, 1H), 7.10-7.30 (m, 9H),
7.46-7.56 (m, 5H), 7.98-8.06 (m, 1H), 8.49 (dd, J=4.8, 0.8 Hz, 1H),
8.74 (d, J=1.2 Hz, 1H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
22.6, 26.9, 34.9, 37.8, 40.9, 47.0, 52.6, 58.3, 58.7, 62.4, 63.0,
73.9, 79.5, 125.3, 125.5, 126.2, 127.5, 127.9, 128.8, 128.85,
131.5, 131.6, 136.4, 137.6, 138.2, 138.4, 138.8, 141.6, 142.5,
148.3, 148.6, 158.9, 171.8, 177.3.
Biological Examples
Extensive guidance on the assay of test compounds at the enzyme
level and in cell culture, including the isolation and/or selection
of mutant HIV strains and mutant RT are found in DAIDS Virology
Manual for HIV Laboratories complied by Division of AIDS, NIAID USA
1997. Resistance studies, including rational for various drug
escape mutants is described in the HIV Resistance Collaborative
Group Data Analysis Plan for Resistance Studies, revised 31 Aug.
1999 and subsequently.
Cellular Assay
Compounds of the invention are assayed for HIV activity, for
example using multiple determinations with XTT in MT-4 cells
(Weislow et al, J Nat Cancer Inst 1989, vol 81 no 8, 577 et seq),
preferably including determinations in the presence of 40-50% human
serum to indicate the contribution of protein binding. In short the
XTT assay uses human T cell line MT4 cells grown in RPMI 1640
medium supplemented with 10% fetal calf serum (or 40-50% human
serum as appropriate), penicillin and streptomycin seeded into 96
well microplates (210.sup.4 cells/well) infected with 10-20
TCID.sub.50 per well of HIV-1.sub.IIIB (wild type) or mutant virus,
such as those bearing RT Ile 100, Cys 181 or Asn 103 mutations.
Serially diluted test compounds are added to respective wells and
the culture incubated at 37.degree. C. in a CO.sub.2 enriched
atmosphere and the viability of cells is determined at day five or
six with XTT vital dye. Results are typically presented as
ED.sub.50 .mu.M.
Expression of HIV-1 protease suitable for enzyme determination is
also described in Danielsson et al. Adv. Exp. Med. Biol., 1998,
436, 99-103. Fluorometric assays for Ki determinations are also
described in Antimicrob. Agents Chemother., 1997, 41, 2383-2388.
This journal also describes a cellular assay for ED50 using MT4
cells and a colorimetric XTT assay.
Time to Resistance
2.times.10.sup.4 MT4 cells per well in a microtitre plate are
infected with 5-10 TCID.sub.50 of HIV-1.sub.IIIB. The compounds
being tested are added at concentrations around ED.sub.50 using 8
duplicates per concentration. After 6 days of incubation the RT
activity in 10 .mu.L supernatant is measured.
The following procedure is followed at subsequent passages of the
cultures once per week. Virus produced at the concentration of test
compound showing >50% of the RT activity of untreated infected
cells (SIC, Starting Inhibitory Concentration) are passaged to
fresh MT4 cells. 15 .mu.L supernatant from each of the eight
duplicates are transferred to cells without the test compound
(control) and to cells with test compound at the same
concentration, and additionally two respectively fivefold higher
concentrations. (See Table 2 below)
When viral growth is permitted at the highest non-toxic
concentration (5-40 .mu.M), 2-4 parallel wells are collected and
expanded to give material for sequence analysis and cross-wise
resistance.
TABLE-US-00001 TABLE 2 Viral growth permitted Virus production
inhibited 125 .times. SIC 125 .times. SIC 25 .times. SIC .fwdarw.
25 .times. SIC 5 .times. SIC 25 .times. SIC 5 .times. SIC .fwdarw.
No compound 25 .times. SIC 5 .times. SIC .fwdarw. No compound 5
.times. SIC SIC SIC .fwdarw. No compound SIC .fwdarw. No compound
Pass 1 Pass 2 Pass 3 Pass 4 Pass 5
P450 Metabolism
The metabolism of compounds of the invention through the main
isoforms of the human cytochrome system P450 are conveniently
determined in baculovirus infected insect cells transfected with
human cytochrome P450 cDNA (supersomes) Gentest Corp. Woburn
USA.
The test compounds at concentrations 0.5, 5 and 50 .mu.M are
incubated in duplicate in the presence of supersomes overexpressing
various cytochrome P450 isoforms, including CYP1A2+P450 reductase,
CYP2A6+P450 reductase, CYP2C9-Arg 144+P450 reductase, CYP2C19+P450
reductase, CYP2D6-Val 374+P450 reductase and CYP3A4+P 450
reductase. Incubates contain a fixed concentration of cytochrome
P450 (eg 50 pmoles) and are conducted over 1 hour. The involvement
of a given isoform in the metabolism of the test compound is
determined by UV HPLC chromatographically measuring the
disappearance of parent compound.
For example, the following table shows the K.sub.1 and ED.sub.50
figures for a representative selection of compounds according to
the invention. Category A indicates a Ki of <10 nM inhibition,
category B indicates 11-50 nM inhibition and category C indicates
50-100 nM inhibition, category D indicates an ED.sub.50<2 .mu.M,
category E indicates 2-10 .mu.M and category E indicates >10
.mu.M:
TABLE-US-00002 TABLE 1 Enzyme Inhibition and Antiviral Activity in
Cell Culture..sup.a Compound Structure K.sub.i (nM) ED.sub.50
(.mu.M) 11 ##STR00127## B F 13 ##STR00128## B F 14 ##STR00129## A E
15 ##STR00130## A E 17 ##STR00131## C F 18 ##STR00132## B F 19
##STR00133## A D 20 ##STR00134## B F
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